Compounds and methods for making and using same

ABSTRACT

In accordance with this invention novel compounds are provided that are selected from saturated and unsaturated pyrans and furans substituted with at least a phosphonate group and a heterocyclic base. These compounds are useful as antiinfectives, flame retardants, diagnostic oligonucleotides and immunogens.

This is a divisional of application Ser. No. 08/615,669 filed on Mar.13, 1996 which is a divisional of Ser. No. 08/384,504 filed on Feb. 1,1995 now U.S. Pat. No. 5,659,023.

This application is cross referenced to related copending applicationSer. No. 08/615,670 filed on Mar. 13, 1996.

This application relates to nucleotide analogues and to their use indiagnostic and therapeutic methods. It relates to immunogens andoligonucleotides containing such nucleotide analogues.

Nucleotide analogues containing phosphonate groups are disclosed forexample in U.S. Pat. Nos. 4,659,825, 4,808,716, 4,724,233, 5,142,051,5,302,585, 5,208,221, 5,352,786, 5,356,886 and in EP publication numbers269,947, 481,214, 630,381, 369,409, 454,427 and 618,214. EP 398,231discloses a structure ##STR1## where B is a purine or pyrimidine base, Xand X¹ are H or C₁ -C₆ alkyl, the broken line designates an optionaldouble bond, Y and X are unsubstituted or substituted C₁ -C₆ alkyl ortogether they constitute an oxygen atom or methylene group in whichevent the broken line is a single bond.

Verheggen et al. "J. Med. Chem." 36:2033-2040 (1993) disclose variousantiviral pyrans as shown below ##STR2## wherein B are definedpyrimidine and purine heterocycles and X is a defined heterogroup.Verheggen et al. disclose the 4-hydroxymethyl and 4-phosphonylmethoxyanalogues of compound (b).

U.S. Pat. No. 5,276,143 discloses incorporating certaindideoxyfructonucleosides and deoxyfructonucleotides intooligonucleotides.

U.S. Pat. No. 5,314,893 discloses various antiviral tetrahydropyrans.

It is an object of this invention to provide antiviral compounds havingan improved selectivity index, i.e., that are less toxic yet moreefficacious than nucleotide analogues known heretofore.

It is another object to prepare compounds that are suitable forfacilitating the labelling of oligonucleotide probes and polypeptides.

It is an additional object to provide compounds useful in thepreparation of fire retardant resins.

It is a further object to obtain nucleotide analogues that are useful asanti-infective agents.

SUMMARY OF THE INVENTION

The objects of this invention are accomplished by novel compounds havingstructure (1) ##STR3## wherein the dashes indicate the positions ofoptional double bonds;

# designates chiral centers, which are numbered;

n is 0 or 1;

Y independently is OH, --OR³, --OCH(R³)OC(O)R³, an oligonucleotide,--OPRT, a monophosphate, a diphosphate, an amino acid amidate, apolypeptide amidate, --NHR³, or --N(R³);

PRT is a protecting group;

Z is CH₂ OR², halo substituted C₁ -C₂ alkyl, CH═CH₂, C.tbd.CH, --CH₂ N₃,CH₃, a detectable label or H;

B is a heterocyclic base;

R^(1a) and R^(1b) independently are H, CN, N₃, halo, OR², C₁ -C₃ alkylor C₁ -C₃ alkyl substituted by N₃, OH, halo, CN or OR², or R^(1a) andR^(1b) may be joined together to form a 1,2-diol protecting group, abond, or --CH₂ --;

R^(1c) is H or, when R^(1a) and R^(1b) are joined together to form abond, R^(1c) is H or F;

R^(1d) and R^(1e) are H or may be joined together to form a bond;

R² independently is H, --C(O)R³, PRT, an oligonucleotide, amonophosphate or a diphosphate;

R³ independently is unsubstituted alkyl, aryl, alkenyl, alkynyl,alkaryl, alkynylaryl or alkenylaryl; said groups where H is substitutedby halo, carboxy, hydroxyl, cyano, nitro, N-morpholino, or amino; and/orsaid groups where --CH₂ -- has been substituted by NH, S, or O;

Z and one Y group may be joined together to form a ring if Z is CH₂ OHand Y is OH;

one Y group and R^(1a) or R^(1b) may be joined together to form a ringif Y is OH and said R^(1a) or R^(1b) group comprises OH, provided thatring positions 1-2 of the furan or pyran ring are saturated and, whenR^(1a) is OH which is cyclized with Y, then R^(1a) and the P atom arelocated on the same side of the ring;

when Y and Z or Y and R^(1a) or R^(1b) form a ring, the P atom becomeschiral center #6;

when n=1 the pyran ring is saturated or is unsaturated at the 1-2 or 2-3positions;

when n=0, R^(1d) and R^(1e) are H; and

the salts thereof.

In another embodiment of the invention a method is provided for thedetection of a target nucleic acid sequence comprising:

(a) providing a labelled oligonucleotide probe having structure (1)##STR4## wherein the dashes indicate the positions of optional doublebonds;

# designates chiral centers, which are numbered;

n is 0 or 1;

Y independently is OH, --OR³, --OCH(R³)OC(O)R³, an oligonucleotide,--OPRT, a monophosphate, a diphosphate, an amino acid amidate, apolypeptide amidate, --NHR³, or --N(R³);

PRT is a protecting group;

Z is CH₂ OR², halo substituted C₁ -C₂ alkyl, CH═CH₂, C.tbd.CH, --CH₂ N₃,CH₃, a detectable label or H;

B is a heterocyclic base;

R^(1a) and R^(1b) independently are H, CN, N₃, halo, OR², C₁ -C₃ alkylor C₁ -C₃ alkyl substituted by N₃, OH, halo, CN or OR², or R^(1a) andR^(1b) may be joined together to form a 1,2-diol protecting group, abond, or --CH₂ --;

R^(1c) is H or, when R^(1a) and R^(1b) are joined together to form abond, R^(1c) is H or F;

R^(1d) and R^(1e) are H or may be joined together to form a bond;

R² independently is H, --C(O)R³, PRT, an oligonucleotide, amonophosphate or a diphosphate;

R³ independently is unsubstituted alkyl, aryl, alkenyl, alkynyl,alkaryl, alkynylaryl or alkenylaryl; said groups where H is substitutedby halo, carboxy, hydroxyl, cyano, nitro, N-morpholino, or amino; and/orsaid groups where --CH₂ -- has been substituted by NH, S, or O;

Z and one Y group may be joined together to form a ring if Z is CH₂ OHand Y is OH;

one Y group and R^(1a) or R^(1b) may be joined together to form a ringif Y is OH and said R^(1a) or R^(1b) group comprises OH, provided thatring positions 1-2 of the furan or pyran ring are saturated and, whenR^(1a) is OH which is cyclized with Y, then R^(1a) and the P atom arelocated on the same side of the ring;

when Y and Z or Y and R^(1a) or R^(1b) form a ring, the P atom becomeschiral center #6;

when n=1 the pyran ring is saturated or is unsaturated at the 1-2 or2-3-positions;

when n=0, R^(1d) and R^(1e) are H;

provided that one Y is an oligonucleotide having a sequence that iscomplementary to that of the target sequence; and

the salts thereof;

(b) hybridizing the labelled oligonucleotide probe to the target nucleicacid; and

(c) detecting the bound labelled oligonucleotide probe.

A further embodiment provides a method for treatment of viral infectionscomprising administering to a subject a therapeutically effective amountof a compound having structure (1) ##STR5## wherein #, B, Y, Z, R^(1a),R^(1b), R^(1c), R^(1d), R^(1e), n and the dashed lines are definedabove.

The invention herein also includes novel synthetic methods. One suchmethod comprises

(a) providing a compound having structure (I) ##STR6## wherein PRT isdefined above, and Z is CH₂ OPRT, halo-substituted C₁ -C₂ alkyl, CH═CH₂,C.tbd.CH, --CH₂ N₃, CH₃ or H;

(b) reacting the compound of structure (I) with P(OPRT)₃ in the presenceof a Lewis Acid; and

(c) recovering from the reaction mixture of step (b) a compound havingstructure (II) ##STR7## This method is unexpectedly superior to the samemethod using dialkyl phosphonic acid in that far less by-products areproduced and yields accordingly increase from about 20% to greater thanabout 90%.

Another method of this invention also relates to double bond migrationin pyranose derivatives. It comprises

(a) providing a compound having structure (III) ##STR8## (b) treatingthe compound with a base; and (c) recovering from the reaction mixtureof step (b) a compound having structure (IV) ##STR9## wherein B isdefined above, and Z and PRT are defined in the preceding method.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, and unless modified by the immediate context: 1. Alkylmeans C₁ -C₁₅ branched, normal or cyclic saturated hydrocarbons andincludes methyl, ethyl, propyl, cyclopropyl, isopropyl, n-, sec-, iso-and tertbutyl, cyclobutyl and the like. 2. Alkenyl means C₂ -C₁₅branched, normal or cyclic hydrocarbons containing at least 1 (generally1-3) cis or trans oriented conjugated or unconjugated double bond,including ethenyl, propenyl, isopropenyl, 1-, 2- and 3-butenyl, 1- and2-isobutenyl and the like. 3. Alkynyl means C₂ -C₁₅ branched, normal, orcyclic hydrocarbons bearing at least 1 (generally 1-3) triple bond,e.g., 2-propynyl. 4. Aryl means an unsaturated resonant cyclic or fusedpolycyclic ring structure containing at least one 3-6 membered ringcontaining ring atoms solely of carbon or of carbon and at least one N-,S- or O- heteroatom, including phenyl, 2- and 3-pyrrolyl, 2- and3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and4-isoxazolyl, 2-, 4-and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and4-pyrazolyl, 2-, 3- and 4-pyridinyl or 2-, 4- and 5-pyrimidinyl. 5.Alkenylaryl means alkenyl substituted with at least 1 (generally 1-3)aryl group and bonded through the alkenyl or aryl moiety to theremainder of the compound through saturated or unsaturated carbon. 6.Alkynylaryl means alkynyl substituted with at least 1 (generally 1-3)aryl group and bonded through the alkenyl or aryl moiety to theremainder of the compound through saturated or unsaturated carbon.

Stereochemistry is depicted according to carbohydrate convention withthe furan or pyran oxygen at the rear of the molecule, and thestereoconfiguration of the substituents indicated by their positionabove and below the plane of the ring. The bonds that project from theside of the ring (substituents of unsaturated ring carbon atoms) arecoplanar with the ring (unless indicated to the contrary by the bonddesignation α, which designates the genus of diastereomers andracemates). Hydrogen atoms bound to ring carbons may not show but shallbe understood to occupy any undesignated valence of the ring carbonatoms. Such hydrogen atoms generally are in the opposite configurationof any group or atom that also may be bound to the same saturated carbonatom.

Group Z typically is CH₂ OH, CH₂ OR², H, CH₃ or vinyl. Generally, it isin the D configuration, but may be in the L configuration or racemic.When Z contains a reactive functionality like OH the reactive groupgenerally is protected (see infra) throughout the synthesis, and isdeprotected as one of the last steps in the synthesis. Thus in CH₂ OR²,R² commonly is PRT. Z is a convenient site for the attachment ofoligonucleotide or of detectable moieties such as biotin, fluorescentgroups and the like using methods known per se. In other embodimentswhere Z is CH₂ OH, Z is internally cyclized by dehydration with ahydroxyl group of the phosphonate, whereby compounds having the partialstructure (2) are obtained (the omitted structural subunit is found instructure (1); in this and the following structures where R^(1c), R^(1d)and R^(1e) are not depicted they are H or a bond as dictated by theircontext): ##STR10## wherein Y and R^(1a) are defined above.

Groups R^(1a) and R^(1b) are saturated C atom substituents or are takentogether to form a bond. R^(1a) or R^(1b) groups typically will beselected from H, OR², OH, lower alkyl, azido or fluoro. An atomic R^(1a)substituent is not bound to an unsaturated C atom. Either the (R) or (S)configuration of R^(1a) or R^(1b) are acceptable, and R^(1a) and R^(1b)may possess the same or different stereochemistry. R^(1a) or R^(1b),like Y or Z, is a convenient site for substitution of an oligonucleotideor a detectable label for use in diagnostics.

In one embodiment of the invention at least one R^(1a) or R^(1b) is OHand is internally cyclized by dehydration with a hydroxyl group of thephosphonate, whereby compounds having the partial structures (3) or (4)are obtained. ##STR11## wherein Y, n, R^(1a) and R^(1b) are definedabove. Cyclization introduces chirality into the P atom, designated #6.Y in structures (2)-(4) is (R) or (S), or may be racemic. The cyclicoxygen atom in structure (3) will be located on the same side of theplane of the furan or pyran ring as the phosphorous atom.

R^(1c) typically is H, whether R^(1a) and R^(1b) are joined to form abond or not, but may be fluoro when R^(1a) and R^(1b) form a bond.R^(1d) and R^(1e) typically are H, but may be joined together to form abond. When n=1, only one of R^(1a) and R^(1b) or R^(1d) and R^(1e) maybe taken together to form a bond; when n=0, R^(1d) and R^(1e) are H.

n. In general the pyranose ring is preferred, i.e., n=1. Moreover,preferably the 2-3 carbon bond of this ring is a double bond.

Group R² typically is H or an ester-forming group --C(O)R³ bound to anyone or more of the pyran or furan hydroxyl substituents R^(1a), R^(1b)or Z. Synthetic reactions may require that R² =PRT. R² is not criticaland can vary widely. Principally, R² groups serve as protecting groupsduring synthetic reactions or groups that are capable of cleavage invivo (generally, esters) to yield the free hydroxyl. Note that some--C(O)R³ are capable of acting as PRT (see infra).

Group R³ also is not a critical functionality and may vary widely. R³for example includes C₃ -C₆ aryl (including phenyl, 2- and 3-pyrrolyl,2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and4-isoxazolyl, 2-, 4-and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and4-pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4- and5-pyrimidinyl), C₃ -C₆ aryl substituted with halo, alkyl C₁ -C₁₂ alkoxy,CN, NO₂, OH, carboxy, carboxyester, thiol, thiolester, C₁ -C₁₂ haloalkyl(1-6 halogen atoms), C₂ -C₁₂ alkenyl or C₂ -C₁₂ alkynyl including 2-, 3-and 4-alkoxyphenyl (C₁ -C₁₂ alkyl), 2-, 3- and 4-methoxyphenyl, 2-, 3-and 4-ethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-diethoxyphenyl,2- and 3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-4-hydroxyphenyl,2- and 3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6-hydroxyphenyl, 2-, 3-and 4-O-acetylphenyl, 2-, 3- and 4-dimethylaminophenyl, 2-, 3- and4-methylmercaptophenyl, 2-, 3- and 4-halophenyl (including 2-, 3- and4-fluorophenyl and 2-, 3- and 4-chlorophenyl!, 2,3-, 2,4-, 2,5-, 2,6-,3,4- and 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and3,5-biscarboxyethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dihalophenyl(including 2,4-difluorophenyl and 3,5-difluorophenyl), 2-, 3-and4-haloalkylphenyl (1 to 5 halogen atoms, C₁ -C₁₂ alkyl including4-trifluoromethylphenyl), 2-, 3- and 4-cyanophenyl, 2-, 3- and4-nitrophenyl, 2-, 3- and 4-haloalkylbenzyl (1 to 5 halogen atoms, C₁-C₁₂ alkyl including 4-trifluoromethylbenzyl and 2-, 3- and4-trichloromethylphenyl and 2-, 3- and 4-trichloromethylphenyl),4-N-methylpiperidinyl, 3-N-methylpiperidinyl, 1-ethylpiperazinyl,benzyl, alkylsalicylphenyl (C₁ -C₄ alkyl, including 2-, 3- and4-ethylsalicylphenyl), 2-,3- and 4-acetylphenyl, 1,8-dihydroxynaphthyl(--O--C₁₀ H₆ --OH) and aryloxy ethyl C₆ -C₉ aryl (including phenoxyethyl)!, 2,2'-dihydroxybiphenyl, alkoxy ethyl C₁ -C₆ alkyl including--CH₂ --CH₂ --O--CH₃ (methoxy ethyl)!, alkyl substituted by OH or by 1to 3 halo atoms (including --CH₃, --CH(CH₃)₂, --C(CH₃)₃, --CH₂ CH₃,--(CH₂)₂ CH₃, --(CH₂)₃ CH₃, --(CH₂)₄ CH₃, --(CH₂)₅ CH₃, --CH₂ CH₂ F,--CH₂ CH₂ Cl, --CH₂ CF₃, and --CH₂ CCl₃), 2-, 3- and4-N,N-dialkylaminophenol, --C₆ H₄ CH₂ --N(CH₃)₂, ##STR12##-N-2-propylmorpholino, 2,3-dihydro-6-hydroxyindene, sesamol, catecholmonoester, --CH₂ --C(O)--N(R¹⁵)₂ wherein each R¹⁵ is the same ordifferent H or C₁ -C₄ alkyl, --CH₂ --S(O)(R¹⁵), --CH₂ --S(O)₂ (R¹⁵),--CH₂ --CH(OC(O)CH₂ R¹⁵)--CH₂ (OC(O)CH₂ R¹⁵), cholesteryl, a 5 or 6carbon monosaccharide, disaccharide or oligosaccharide (3 to 9monosaccharide residues), enolpyruvate (HOOC--C(═CH₂)O), glycerol,α-D-β-diglycerides (wherein the fatty acids composing glyceride lipidsgenerally are naturally occurring saturated or unsaturated C₆ -₂₆, C₆-₁₈ or C₆ -₁₀ fatty acids such as linoleic, lauric, myristic, palmitic,stearic, oleic, palmitoleic, linolenic and the like fatty acids),trimethoxybenzyl, triethoxybenzyl, 2-alkyl pyridinyl (C₁ -₄ alkyl),##STR13## C₁ -C₄ alkylene-C₃ -C₆ aryl (including benzyl, --CH₂-pyrrolyl, --CH₂ -thienyl, --CH₂ -imidazolyl, --CH₂ -oxazolyl, --CH₂-isoxazolyl, --CH₂ -thiazolyl, --CH₂ -isothiazolyl, --CH₂ -pyrazolyl,--CH₂ -pyridinyl and --CH₂ -pyrimidinyl) substituted in the aryl moietyby 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen,C₁ -C₁₂ alkoxy (including methoxy and ethoxy), cyano, nitro, OH, C₁ -C₁₂haloalkyl (1 to 6 halogen atoms; including --CH₂ -CCl₃), C₁ -C₁₂ alkyl(including methyl and ethyl), C₂ -C₁₂ alkenyl or C₂ -C₁₂ alkynyl, andother compounds set forth in Table 7 below. The hydroxyl groups of Z,R^(1a) and/or R^(1b) optionally are substituted with one of groups III,IV or V disclosed in WO94/21604.

PRT is a protecting group used to prevent side reactions with theprotected group during synthetic procedures. For the most part thedecision as to which groups to protect, when to do so, and the nature ofthe PRT will be dependent upon the chemistry of the reaction to beprotected against (e.g., acidic, basic, oxidative, reductive or otherconditions) and the intended direction of the synthesis. The PRT groupsdo not need to be, and generally are not, the same if the compound issubstituted with multiple PRT. In general, PRT will be used to protecthydroxyl or amino groups. The latter are found on some heterocyclicbases, while hydroxyl PRT (--OPRT) are used to protect Y, R¹ and Zhydroxyl groups. The order of deprotection to yield free hydroxyl alsois dependent upon the intended direction of the synthesis and thereaction conditions to be encountered. Typically the Z, B, Y and R¹groups all will be protected and thereafter will be deprotected in anyorder as required. For example, heterosubstitution at the R¹ groupsgenerally will require that one R¹ OH be unprotected or differentlyprotected than the other R¹ (see scheme 1). In other embodiments, the Yhydroxyl groups and/or B amino groups are not protected but Z and R¹ are--CH₂ OPRT or --OPRT, respectively.

A very large number of hydroxy protecting groups and correspondingchemical cleavage reactions are described in "Protective Groups inOrganic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., NewYork, 1991, ISBN 0-471-62301-6) ("Greene"). As will be seen from thediscussion below, some R³ groups described above also are capable ofacting as PRT.

Typical hydroxy protecting groups are described in Greene at pages14-118 and include Ethers (Methyl); Substituted Methyl Ethers(Methoxymethyl, Methylthiomethyl, t-Butylthiomethyl,(Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl,p-Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl,t-Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl,2-Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl,Bis(2-chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl,Tetrahydropyranyl, 3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl,1-Methoxycyclohexyl, 4-Methoxytetrahydropyranyl,4-Methoxytetrahydrothiopyranyl, 4-MethoxytetrahydropthiopyranylS,S-Dioxido, 1- (2-Chloro-4-methyl)phenyl!-4-methoxypiperidin-4-yl, 35,1,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-Octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl));Substituted Ethyl Ethers (1-Ethoxyethyl, 1-(2-Chloroethoxy)ethyl,1-Methyl-1-methoxyethyl, 1-Methyl-1-benzyloxyethyl,1-Methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-Trichloroethyl,2-Trimethylsilylethyl, 2-(Phenylselenyl)ethyl, t-Butyl, Allyl,p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl); SubstitutedBenzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl,p-Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl, p-Cyanobenzyl,p-Phenylbenzyl, 2- and 4-Picolyl, 3-Methyl-2-picolyl N-Oxido,Diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-Dibenzosuberyl,Triphenylmethyl, α-Naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl,Tri(p-methoxyphenyl)methyl, 4-(4'-Bromophenacyloxy)phenyldiphenylmethyl,4,4',4"-Tris(4,5-dichlorophthalimidophenyl)methyl,4,4',4"-Tris(levulinoyloxyphenyl)methyl,4,4',4"-Tris(benxoyloxyphenyl)methyl,3-(Imidazol-1-ylmethyl)bis(4',4"-dimethoxyphenyl)methyl,1,1-Bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-Anthryl,9-(9-Phenyl)xanthenyl, 9-(9-Phenyl-10-oxo)anthryl,1,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S-Dioxido); Silyl Ethers(Trimethylsilyl, Triethylsilyl, Triisopropylsilyl,Dimethylisopropylsilyl, Diethylisopropylsily, Dimethylthexylsilyl,t-Butyldimethylsilyl, t-Butyldiphenylsilyl, Tribenzylsilyl,Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl,t-Butylmethoxyphenylsilyl); Esters (Formate, Benzoylformate, Acetate,Choroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate,Methoxyacetate, Triphenylmethoxyacetate, Phenoxyacetate,p-Chlorophenoxyacetate, p-poly-Phenylacetate, 3-Phenylpropionate,4-Oxopentanoate (Levulinate), 4,4-(Ethylenedithio)pentanoate, Pivaloate,Adamantoate, Crotonate, 4-Methoxycrotonate, Benzoate, p-Phenylbenzoate,2,4,6-Trimethylbenzoate (Mesitoate)); Carbonates (Methyl,9-Fluorenylmethyl, Ethyl, 2,2,2-Trichloroethyl, 2-(Trimethylsilyl)ethyl,2-(Phenylsulfonyl)ethyl, 2-(Triphenylphosphonio)ethyl, Isobutyl, Vinyl,Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl, 3,4-Dimethoxybenzyl,o-Nitrobenzyl, p-Nitrobenzyl, S-Benzyl Thiocarbonate,4-Ethoxy-1-naphthyl, Methyl Dithiocarbonate); Groups With AssistedCleavage (2-Iodobenzoate, 4-Azidobutyrate, 4-Niotro-4-methylpentanoate,o-(Dibromomethyl)benzoate, 2-Formylbenzenesulfonate,2-(Methylthiomethoxy)ethyl Carbonate, 4-(Methylthiomethoxy)butyrate,2-(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters(2,6-Dichloro-4-methylphenoxyacetate,2,6-Dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-Bis(1,1-dimethylpropyl)phenoxyacetate, Chorodiphenylacetate,Isobutyrate, Monosuccinoate, (E)-2-Methyl-2-butenoate (Tigloate),o-(Methoxycarbonyl)benzoate, p-poly-Benzoate, α-Naphthoate, Nitrate,Alkyl N,N,N',N'-Tetramethylphosphorodiamidate, N-Phenylcarbamate,Borate, Dimethylphosphinothioyl, 2,4-Dinitrophenylsulfenate); andSulfonates (Sulfate, Methanesulfonate (Mesylate), Benzylsulfonate,Tosylate).

More typically, hydroxy protecting groups include substituted methylethers, substituted benzyl ethers, silyl ethers, and esters includingsulfonic acid esters, still more typically, trialkylsilyl ethers,tosylates and acetates.

Typical 1,2-diol protecting groups (thus, generally where two R¹ OHgroups are taken together with a protecting functionality) are describedin Greene at pages 118-142 and include Cyclic Acetals and Ketals(Methylene, Ethylidene, 1-t-Butylethylidene, 1-Phenylethylidene,(4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide(Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene,Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene,3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters(Methoxymethylene, Ethoxymethylene, Dimethoxymethylene,1-Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene,(α-Methoxybenzylidene, 1-(N,N-Dimethylamino)ethylidene Derivative,α-(N,N-Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene);Silyl Derivatives (Di-t-butylsilylene Group,1,3-(1,1,3,3-Tetraisopropyldisiloxanylidene), andTetra-t-butoxydisiloxane-1,3-diylidene), Cyclic Carbonates, CyclicBoronates, Ethyl Boronate and Phenyl Boronate.

More typically, 1,2-diol protecting groups include those shown in Table1a, still more typically, epoxides, acetonides, cyclic ketals and arylacetals.

                  TABLE 1a                                                        ______________________________________                                         ##STR14##                                                                     ##STR15##                                                                     ##STR16##                                                                     ##STR17##                                                                     ##STR18##                                                                    ______________________________________                                    

wherein R¹⁴ is C₁ -C₆ alkyl.

Group Y typically will be OH or convertible to OH by chemical orbiological means. For in vivo hydrolysis Y usually is OR³ in which R³ isphenyl or substituted phenyl as described below or Y is--OCH(R³)OC(O)R³. Y is OPRT in intermediates for the most part. Certainend uses for intermediate compounds of the invention contemplate Y=anoligonucleotide or protein.

Particularly useful Y groups are alkylacyloxymethyl groups and theirderivatives, including --CH(CH₂ CH₂ OCH₃)OC(O)C(CH₃)₃, ##STR19## --CH₂OC(O)C₁₀ H₁₅, --CH₂ OC(O)C(CH₃)₃, --CH(CH₂ OCH₃)OC(O)C(CH₃)₃,--CH(CH(CH₃)₂)OC(O)C(CH₃)₃, --CH₂ OC(O)CH₂ CH(CH₃)₂, --CH₂ OC(O)C₆ H₁₁,--CH₂ OC(O)C₆ H₅, --CH₂ OC(O)C₁₀ H₁₅, --CH₂ OC(O)CH₂ CH₃, --CH₂OC(O)CH(CH₃)₂, --CH₂ OC(O)C(CH₃)₃ and --CH₂ OC(O)CH₂ C₆ H₅.

Y also may be an amino acid residue. In general, the amino acid residuehas the structure R⁴ OC(O)CH(R⁵)NH--, where R⁴ is R³, one or moreadditional amino acid residues linked via peptide bonds, or H and R⁵ isalkyl substituted with amino, carboxyl, amide, carboxyl ester, hydroxyl,C₆ -C₇ aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide,and/or alkylphosphate. Ordinarily R⁴ is R³ and R⁵ is a side chain of anaturally occurring amino acid. With respect to the carboxyl-containingside chains it will be understood that if the C atom of the subjectcarboxyl is linked by 5 or less atoms to the phosphoamide N then thecarboxyl optionally will be blocked, e.g. by esterification with R³ oramidation wherein the ester or amide bonds are hydrolyzable in vivo. R⁵also is taken together with the amino acid α N to form a proline residue(R⁵ =--CH₂)₃ --). However, R⁵ is generally a side group such as H,--CH₃, --CH(CH₃)₂, CH₂ --CH(CH₃)₂, --CHCH₃ --CH₂ CH₃, --CH₂ --C₆ H₅,--CH₂ CH₂ --S--CH₃, --CH₂ OH, --CH(OH)--CH₃, --CH₂ --SH, --CH₂ --C₆ H₄OH, --CH₂ --CO--NH₂, --CH₂ --CH₂ --CO--NH₂, --CH₂ --COOH, --CH₂ --CH₂--COOH, --(CH₂)₄ --NH₂ and --(CH₂)₃ --NH--C(NH₂)--NH₂. R⁵ also includes1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl,indol-3-yl, methoxyphenyl and ethoxyphenyl.

When the amino acid residue contains one or more chiral centers, any ofthe D, L, meso, threo or erythro (as appropriate) racemates, scalematesor mixtures thereof may be used as group Y. In general, if theintermediates are to be hydrolyzed non-enzymatically (as would be thecase where the compounds are used as chemical intermediates for the freeacids), D isomers are useful. On the other hand, L isomers are moreversatile since they can be susceptible to both non-enzymatic andenzymatic hydrolysis, and are more efficiently transported by amino acidor dipeptidyl transport systems in the gastrointestinal tract.

Examples of suitable amino acid residues include the following:

Glycyl;

Aminopolycarboxylic acids, e.g., aspartic acid, β-hydroxyaspartic acid,glutamic acid, β-hydroxyglutamic acid, β-methylaspartic acid,β-methylglutamic acid, β,β-dimethylaspartic acid, γ-hydroxyglutamicacid, β,γ-dihydroxyglutamic acid, β-phenylglutamic acid,γ-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid,2-aminosuberic acid and 2-aminosebacic acid residues;

Amino acid amides such as glutaminyl and asparaginyl;

Polyamino- or polybasic-monocarboxylic acids such as arginine, lysine,β-aminoalanine, γ-aminobutyrine, ornithine, citruline, homoarginine,homocitrulline, 5-hydroxy-2,6-diaminohexanoic acid (commonly,hydroxylysine, including allohydroxylysine), diaminobutyric andhistidine residues;

Diaminodicarboxylic acids such as α,α'-diaminosuccinic acid,α,α'-diaminoglutaric acid, α,α'-diaminoadipic acid, α,α'-diaminopimelicacid, α,α'-diamino-β-hydroxypimelic acid, α,α'-diaminosuberic acid,α,α'-diaminoazelaic acid, and α,α'-diaminosebacic acid residues;

Imino acids such as proline, 4- or 3-hydroxy-2-pyrrolidinecarboxylicacid (commonly, hydroxyproline, including allohydroxyproline),γ-methylproline, pipecolic acid, 5-hydroxypipecolic acid, -N( CH₂ !_(n)COOR³)₂, wherein n and R³ are as defined above, andazetidine-2-carboxylic acid residues;

A mono- or di-alkyl (typically C₁ -C₈ branched or normal) amino acidsuch as alanine, valine, leucine, allylglycine, butyrine, norvaline,norleucine, heptyline, α-methylserine, α-amino-α-methyl-γ-hydroxyvalericacid, α-amino-α-methyl-δ-hydroxyvaleric acid,α-amino-α-methyl-ε-hydroxycaproic acid, isovaline, α-methylglutamicacid, α-aminoisobutyric acid, α-aminodiethylacetic acid,α-aminodiisopropylacetic acid, α-aminodi-n-propylacetic acid,α-aminodiisobutylacetic acid, α-aminodi-n-butylacetic acid,α-aminoethylisopropylacetic acid, α-amino-n-propylacetic acid,α-aminodiisoamyacetic acid, α-methylaspartic acid, α-methylglutamicacid, 1-aminocyclopropane-1-carboxylic acid; isoleucine, alloisoleucine,tert-leucine, β-methyltryptophan and α-amino-β-ethyl-β-phenylpropionicacid residues; β-phenylserinyl;

Aliphatic α-amino-β-hydroxy acids such as serine, β-hydroxyleucine,β-hydroxynorleucine, β-hydroxynorvaline, and α-amino-β-hydroxystearicacid residues;

α-Amino, α-, γ-, δ- or ε-hydroxy acids such as homoserine,γ-hydroxynorvaline, δ-hydroxynorvaline and epsilon-hydroxynorleucineresidues; canavinyl and canalinyl; γ-hydroxyornithinyl;

2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminic acidresidues;

α-Amino-β-thiols such as penicillamine, β-thiolnorvaline orβ-thiolbutyrine residues;

Other sulfur containing amino acid residues including cysteine;homocystine; β-phenylmethionine; methionine; S-allyl-L-cysteinesulfoxide; 2-thiolhistidine; cystathionine; and thiol ethers of cysteineor homocysteine;

Phenylalanine, tryptophan and ring-substituted α amino acids such as thephenyl- or cyclohexylamino acids α-aminophenylacetic acid,α-aminocyclohexylacetic acid and α-amino-β-cyclohexylpropionic acid;phenylalanine analogues and derivatives comprising aryl, lower alkyl,hydroxy, guanidino, oxyalkylether, nitro, sulfur or halo-substitutedphenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-,3,4-dicloro, o-, m- or p-methyl-, 2,4,6-trimethyl-, 2-ethoxy-5-nitro,2-hydroxy-5-nitro and p-nitrophenylalanine); furyl-, thienyl-, pyridyl-,pyrimidinyl-, purine or naphthylalanines; and tryptophan analogues andderivatives including kynurenine, 3-hydroxykynurenine,2-hydroxytryptophan and 4-carboxytryptophan residues;

α-Amino substituted amino acid residues including sarcosine(N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine,N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline andN-benzylvaline; and

α-Hydroxy and substituted α-hydroxy amino acid residues includingserine, threonine, allothreonine, phosphoserine and phosphothreonineresidues.

Any one of the foregoing or other known amino acids are suitablyemployed in this invention particularly if they are capable ofautocatalytically hydrolyzing the P-amidate bond. Thus, they shouldcontain a free carboxyl group, or should do so upon hydrolysis in vivo.

Of particular interest are hydrophobic residues such as mono-or di-alkylor aryl amino acids, cycloalkylamino acids and the like. These residuescontribute to cell permeability by increasing the partition coefficientof the nucleotide analogue amidate. Typically, the residue does notcontain a sulfhydryl or guanidino substituent.

Y optionally is a polypeptide radical. Polypeptides comprise dipeptides(2 residues), or polypeptides of 3, 5, 10 and up to 100 or moreresidues. They include enzymes (e.g., hydrogen peroxidase) as well asantibodies or proteins of any type against which one wishes to raise animmune response. The nature and identity of the polypeptide may varywidely. The polypeptide optionally contains a peptidolytic enzymecleavage site at the peptide bond between the first and second residuesadjacent to the phosphorus atom. Such cleavage sites are flanked byenzymatic recognition structures, e.g. a particular sequence of residuesrecognized by a peptidolytic enzyme.

Peptidolytic enzymes for cleaving the polypeptide conjugates of thisinvention are well known, and in particular include carboxypeptidases.Carboxypeptidases digest polypeptides by removing C-terminal residues,and are specific in many instances for particular C-terminal sequences.Such enzymes and their substrate requirements in general are well known.For example, a dipeptide (having a given pair of residues and a freecarboxyl terminus) is covalently bonded through its α-amino group to thephosphorus atom of the nucleotide analogue herein. It is expected thatthis peptide will be cleaved by the appropriate peptidolytic enzyme,leaving the carboxyl of the proximal amino acid residue toautocatalytically cleave the amidate bond.

Suitable dipeptidyl groups (designated by their single letter code) areAA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW,AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS,RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF,NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK,DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CH, CI,CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG,EH, El, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE,QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD,GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR,HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT, HW, HY, HV,IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP, IS, IT, IW,IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI,KA, KR, KN, KD, KC, KLS,LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK, KM, KF,KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK,MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, FI,FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG,PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE,SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN, TD,TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY, TV, WA, WR,WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW, WY, WV,YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS, YT, YW,YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS,VT, VW, VY and VV.

Tripeptides are also useful as Y. The sequence -X4-pro-X5- (where X4 isany amino acid residue and X5 is an amino acid residue, a carboxyl esterof proline, or hydrogen) will be cleaved by luminal carboxypeptidase toyield X4 with a free carboxyl, which in turn autocatalytically cleavesthe phosphono amidate bond. X5 usually will be a benzyl ester of thecarboxy group of X5.

Dipeptide or tripeptide species can be selected on the basis of knowntransport properties and/or susceptibility to peptidases that can affecttransport to intestinal mucosal or other cell types. Dipeptides andtripeptides lacking an α-amino group are transport substrates for thepeptide transporter found in brush border membrane of intestinal mucosalcells (Bai, J. P. F., "Pharm Res." 9:969-978 (1992). Transport competentpeptides can thus be used to enhance bioavailability of Y amidatecompounds. Di- or tripeptides having one or more amino acids in the Dconfiguration are also compatible with peptide transport and can beutilized in Y amidate compounds. Amino acids in the D configuration canbe used to reduce the susceptibility of a di- or tripeptide tohydrolysis by proteases common to the brush border such asaminopeptidase N (EC 3.4.11.2). In addition, di- or tripeptides withamino acid residues can be selected on the basis of their relativeresistance to hydrolysis by proteases found in the lumen of theintestine. For example, tripeptides or oligopeptides lacking asp and/orglu are poor substrates for aminopeptidase A (EC 3.4.11.7), di- ortripeptides lacking amino acid residues on the N-terminal side ofhydrophobic amino acids (leu, tyr, phe, val, trp) are poor substratesfor endopeptidase 24.11 (EC 3.4.24.11), and peptides lacking a proresidue at the penultimate position at a free carboxyl terminus are poorsubstrates for carboxypeptidase P (EC 3.4.17). Similar considerationscan also be applied to the selection of peptides that are eitherrelatively resistant or relatively susceptible to hydrolysis bycytosolic, renal, hepatic, serum or other peptidases. Such poorlycleaved polypeptide amidates are immunogens or are useful for bonding toproteins in order to prepare immunogens.

Group B. B is a heterocyclic base. It typically is capable ofparticipating in Watson-Crick base pairing, or is a protected analoguethereof. It includes any naturally-occurring heterocycle found innucleic acids, nucleotides or nucleosides of living organisms. Theheterocyclic bases generally are the purine, pyrimidine or relatedheterocycles shown in formulas (6)-(9). ##STR20## wherein R⁶ is H, OH,F, Cl, Br, I, OR³, SH, SR³, NH₂, or NHR³ ;

R⁷ is N, CF, CCl, CBr, CI, CR⁸, CSR⁸, or COR⁸ ;

R⁸ is H, C₁ -C₉ alkyl, C₂ -C₉ alkenyl, C₂ -C₉ alkynyl or C₇ -C₉aryl-alkyl unsubstituted, or H substituted by OH, F, Cl, Br or I, or CH₂substituted by O, NH or NR³ ; R⁸ includes CH₃, CH₂ CH₃, CHCH₂, CHCHBr,CH₂ CH₂ Cl, CH₂,CH₂ F, CH₂ CCH, CH₂ CHCH₂, C₃ H₇, CH₂ OH, CH₂ OCH₃, CH₂OC₂ H₅, CH₂ OCCH, CH₂ OCH₂ CHCH₂, CH₂ C₃ H₇, CH₂ CH₂ OH, CH₂ CH₂ OCH₃,CH₂ CH₂ OC₂ H₅, CH₂ CH₂ OCCH, CH₂ CH₂ OCH₂ CHCH₂, and CH₂ CH₂ OC₃ H₇ ;

R⁹ is N or CH;

R¹⁰ is N, CH, CCN, CCF₃, CC.tbd.CH or CC(O)NH₂ ;

R¹¹ is H, OH, NH₂, SH, SR³ (such as SCH₃, SCH₂ CH₃, SCH₂ CCH, SCH₂ CHCH₂or SC₃ H₇), NH(R³) (such as NH(CH₃), NH(CH₂ CH₃) NH(CH₂ CCH), NH(CH₂CHCH₂) or NH(C₃ H₇); N(R³)₂ such as N(CH₂ CH₃)₂ ; or halogen (F, Cl, Bror I);

R¹² is H, OH, F, Cl, Br, I, SR³ (such as SCH₃, SCH₂ CH₃, SCH₂ CCH, SCH₂CHCH₂ or SC₃ H₇), OR³, NH₂, N(R³)₂ or NHR³ ; and

R¹³ is O, S or Se.

Specific heterocyclic bases include the purines hypoxanthine, inosine,xanthine, 2-aminopurine, 2,6-diaminopurine, 2-amino-6-chloropurine,adenine, guanine, 6-thio-2-aminopurine and the 8-aza, 7-deaza-8-aza,1-deaza, 7-deaza or 3-deaza derivatives of each of the foregoingpurines; and the pyrimidines cytosine, thymine, uracil, 6-azacytosine;5-fluorocytosine; 5-chlorocytosine; 5-iodocytosine; 5-bromocytosine;5-methylcytosine; 5-bromovinyluracil; 5-fluorouracil; 5-chlorouracil;5-iodouracil; 5-bromouracil; 5-trifluoromethyluracil;5-methoxymethyluracil; 5-ethynyluracil; and 5-propynyluracil. Cytosineor 5-halo- and 5-C₁ -C₅ -alkyl cytosine are preferred where Z=CH₂ OR².For the other Z groups, B ordinarily is a purine or its monoaza ormonodeaza analogue.

B includes both protected and unprotected forms of the heterocyclicbases. Protecting groups for exocyclic amines of heterocyclic bases suchas adenine, cytosine, 2,6-diaminopurine and the like are known. Theselection of a protecting group will be apparent to the ordinary artisanand will depend on the nature of the labile group and the chemistrywhich the protecting group is expected to encounter.

Typical amino protecting groups are described in Greene at pages 315-385and include Carbamates (methyl and ethyl, 9-fluorenylmethyl,9(2-sulfo)fluoroenylmethyl, 9-(2,7-dibromo)fluorenylmethyl,2,7-di-t-buthyl-9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)!methyl,4-methoxyphenacyl); Substituted Ethyl (2,2,2-trichoroethyl,2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl,1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl,1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl,1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2'- and 4'-pyridyl)ethyl,2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl,allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl,N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl,p-nitrobenzyl, p-bromobenzyl, p-chorobenzyl, 2,4-dichlorobenzyl,4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl); Groups WithAssisted Cleavage (2-methylthioethyl, 2-methylsulfonylethyl,2-(p-toluenesulfonyl)ethyl, 2-(1,3-dithianyl)!methyl,4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl,2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl,m-choro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl,5-benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl); GroupsCapable of Photolytic Cleavage (m-nitrophenyl, 3,5-dimethoxybenzyl,o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl,phenyl(o-nitrophenyl)methyl); Urea-Type Derivatives(phenothiazinyl-(10)-carbonyl, N'-p-toluenesulfonylaminocarbonyl,N'-phenylaminothiocarbonyl); Miscellaneous Carbamates (t-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl,2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl,1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl,di(2-pyridyl)methyl, 2-furanylmethyl, 2-Iodoethyl, Isobornyl, Isobutyl,Isonicotinyl, p-(p'-Methoxyphenylazo)benzyl, 1-methylcyclobutyl,1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl,1-methyl-1-(3,5-dimethoxyphenyl)ethyl,1-methyl-1-(p-phenylazophenyl)ethyl, 1-methy-1-phenylethyl,1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl,2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl,2,4,6-trimethylbenzyl); Amides (N-formyl, N-acetyl, N-choroacetyl,N-trichoroacetyl, N-trifluoroacetyl, N-phenylacetyl,N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide,N-benzoylphenylalanyl, N-benzoyl, N-p-phenylbenzoyl); Amides WithAssisted Cleavage (N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl,N-acetoacetyl, (N'-dithiobenzyloxycarbonylamino)acetyl,N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl,N-2-methyl-2-(o-nitrophenoxy)propionyl,N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl,N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine,N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl,4,5-diphenyl-3-oxazolin-2-one); Cyclic Imide Derivatives (N-phthalimide,N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3-5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridonyl); N-Alkyl and N-Aryl Amines (N-methyl, N-allyl,N- 2-(trimethylsilyl)ethoxy!methyl, N-3-acetoxypropyl,N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), Quaternary AmmoniumSalts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl,N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl,N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene,N-ferrocenylmethyl, N-2-picolylamine N'-oxide), Imine Derivatives(N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenylidene,N-diphenylmethylene, N- (2-pyridyl)mesityl!methylene,N,(N',N'-dimethylaminomethylene, N,N'-isopropylidene,N-p-nitrobenzylidene, N-salicylidene, N-5-chlorosalicylidene,N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylidene); EnamineDerivatives (N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)); N-Metal Derivatives(N-borane derivatives, N-diphenylborinic acid derivatives, N-phenyl(pentacarbonylchromium- or -tungsten)!carbenyl, N-copper or N-zincchelate); N-N Derivatives (N-nitro, N-nitroso, N-oxide); N-P Derivatives(N-diphenylphosphinyl, N-dimethylthiophosphinyl,N-diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl,N-diphenyl phosphoryl); N-Si Derivatives; N-S Derivatives; N-SulfenylDerivatives (N-benzenesulfenyl, N-o-nitrobenzenesulfenyl,N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl,N-2-nitro-4-methoxybenzenesulfenyl, N-triphenylmethylsulfenyl,N-3-nitropyridinesulfenyl); and N-sulfonyl Derivatives(N-p-toluenesulfonyl, N-benzenesulfonyl,N-2,3,6-trimethyl-4-methoxybenzenesulfonyl,N-2,4,6-trimethoxybenzenesulfonyl,N-2,6-dimethyl-4-methoxybenzenesulfonyl, N- pentamethylbenzenesulfonyl,N-2,3,5,6,-tetramethyl-4-methoxybenzenesulfonyl,N-4-methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl,N-2,6-dimethoxy-4-methylbenzenesulfonyl,N-2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl,N-β-trimethylsilyethanesulfonyl, N-9-anthracenesulfonyl,N-4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonyl, N-benzylsulfonyl,N-trifluoromethylsulfonyl, N-phenacylsulfonyl).

More typically, protected amino groups include carbamates and amides,still more typically, --NHC(O)R³ or --N═CR⁴ N(R³)₂.

Exemplary Compounds of the Invention

By way of example and not limitation, embodiment compounds are namedbelow in tabular format (Table 5). Generally, each compound is depictedas a substituted nucleus in which the nucleus is designated by capitalletter(s) and each substituent is designated in order by lower caseletter or number. Table 1 is a schedule of nuclei which differprincipally by the position and presence or absence of ringunsaturation, the stereochemistry of the ring substituents, the size ofthe ring and substitution at the 2 and 3 positions. Each nucleus isgiven a numerical designation from Table 1, and this designation appearsfirst in each compound name. Similarly, Tables 2, 3 and 4 list theselected Z, B, R^(1a) and R^(1b) substituents, again by letter or numberdesignation. R^(1c), R^(1d) and R^(1e), if not shown herein, are H orbonds as dictated by valence. Accordingly, each named compound will bedepicted by a number followed by upper and lower case lettersdesignating the Z and B substitutents and, as appropriate, one or twomore numbers designating the R^(1a) and R^(1b) substituents. R^(1a) is Hin structures 19-26. Thus, structure (28), scheme 2, is represented by20.A.c.12 or 26.A.c.12 and compound (30), scheme 2, is represented by9.A.c.12, where B=cytosine.

                  TABLE 1                                                         ______________________________________                                        Nucleus Structures                                                            ______________________________________                                         ##STR21##                                                                     ##STR22##                                                                     ##STR23##                                                                     ##STR24##                                                                     ##STR25##                                                                     ##STR26##                                                                     ##STR27##                                                                     ##STR28##                                                                     ##STR29##                                                                     ##STR30##                                                                     ##STR31##                                                                     ##STR32##                                                                     ##STR33##                                                                     ##STR34##                                                                     ##STR35##                                                                     ##STR36##                                                                     ##STR37##                                                                    ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Group Z                                                                       ______________________________________                                        A.       CH.sub.2 OH E.    CH.sub.2 OCH(CH.sub.3).sub.2                       B.       CH.sub.3    F.    CH.sub.2 OC(O)CH.sub.2 CH.sub.3                    C.       CH.sub.2 F  G.    CH.sub.2 N.sub.3                                   D.       H           H.    CH═CH.sub.2                                                         I.    C.tbd.H                                            ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Group B                                                                       a.     adenin-9-yl     g.    2-aminopurin-9-yl                                b.     guanin-9-yl     h.    3-deazaadenin-9-yl                               c.     cytosin-1-yl    i.    8-azaadenin-9-yl                                 d.     thymin-1-yl     j.    5-iodocytosin-1-yl                               e.     2,6-diaminopurin-9-yl                                                                         k.    7-deazaguanin-9-yl                               f.     5-fluorocytosin-1-yl                                                                          l.    5-chlorocytosin-1-yl                             ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Groups R.sup.1a and R.sup.1b                                                  1.        OH           4.    OCH(CH.sub.3).sub.2                              2.        H            5.    OC(O)CH.sub.3                                    3.        F            6.    CH.sub.3                                                                7.    CH.sub.2 N.sub.3                                                        8.    N.sub.3                                                                 9.    CN                                                                      10.   CH.sub.2 OH                                      ______________________________________                                    

                                      TABLE 5                                     __________________________________________________________________________    Key: Nucleus. Group Z. Group B. Group R.sup.1a. Group Rhu 1b.                 Saturated Pyrans                                                              01.A.a.1.1; 01.A.a.1.2; 01.A.a.1.3; 01.A.a.2.1;.01.A.a.2.2; 01.A.a.2.3;       01.A.a.3.1;                                                                   01.A.a.3.2; 01.A.a.3.3; 01.A.b.1.1; 01.A.b.1.2; 01.A.b.1.3;.01.A.b.2.1;       01.A.b.2.2;                                                                   01.A.b.2.3; 01.A.b.3.1; 01.A.b.3.2; 01.A.b.3.3; 01.A.c.1.1; 01.A.c.1.2;       01.A.c.1.3;                                                                   01.A.c.2.1; 01.A.c.2.2; 01.A.c.2.3; 01.A.c.3.1; 01.A.c.3.2; 01.A.c.3.3;       01.A.d.1.1;                                                                   01.A.d.1.2; 01.A.d.1.3; 01.A.d.2.1; 01.A.d.2.2; 01.A.d.2.3; 01.A.d.3.1;       01.A.d.3.2;                                                                   01.A.d.3.3; 01.A.e.1.1; 01.A.e.1.2; 01.A.e.1.3; 01.A.e.2.1; 01.A.e.2.2;       01.A.e.2.3;                                                                   01.A.e.3.1; 01.A.e.3.2; 01.A.e.3.3; 01.A.f.1.1; 01.A.f.1.2; 01.A.f.1.3;       01.A.f.2.1;                                                                   01.A.f.2.2; 01.A.f.2.3; 01.A.f.3.1; 01.A.f.3.2; 01.A.f.3.3; 01.B.a.1.1;       01.B.a.1.2;                                                                   01.B.a.1.3; 01.B.a.2.1; 01.B.a.2.2; 01.B.a.2.3; 01.B.a.3.1; 01.B.a.3.2;       01.B.a.3.3;                                                                   01.B.b.1.1; 01.B.b.1.2; 01.B.b.1.3; 01.B.b.2.1; 01.B.b.2.2; 01.B.b.2.3;       01.B.b.3.1;                                                                   01.B.b.3.2; 01.B.b.3.3; 01.B.c.1.1; 01.B.c.1.2; 01.B.c.1.3; 01.B.c.2.I;       01.B.c.2.2;                                                                   01.B.c.2.3; 01.B.c.3.1; 01.B.c.3.2; 01.B.c.3.3; 01.B.d.1.1; 01.B.d.1.2;       01.B.d.1.3;                                                                   01.B.d.2.1; 01.B.d.2.2; 01.B.d.2.3; 01.B.d.3.1; 01.B.d.3.2; 01.B.d.3.3;       01.B.e.1.1;                                                                   01.B.e.1.2; 01.B.e.1.3; 01.B.e.2.1; 01.B.e.2.2; 01.B.e.2.3; 01.B.e.3.1;       01.B.e.3.2;                                                                   01.B.e.3.3; 01.B.f.1.1; 01.B.f.1.2; 01.B.f.1.3; 01.B.f.2.1; 01.B.f.2.2;       01.B.f.2.3; 01.B.f.3.1;                                                       01.B.f.3.2; 01.B.f.3.3; 01.C.a.1.1; 01.C.a.1.2; 01.C.a.1.3; 01.C.a.2.1;       01.C.a.2.2;                                                                   01.C.a.2.3; 01.C.a.3.1; 01.C.a.3.2; 01.C.a.3.3; 01.C.b.1.1; 01.C.b.1.2;       01.C.b.1.3;                                                                   01.C.b.2.1; 01.C.b.2.2; 01.C.b.2.3; 01.C.b.3.1; 01.C.b.3.2; 01.C.b.3.3;       01.C.c.1.1;                                                                   01.C.c.1.2; 01.C.c.1.3; 01.C.c.2.1; 01.C.c.2.2; 01.C.c.2.3; 01.C.c.3.1;       01.C.c.3.2;                                                                   01.C.c.3.3; 01.C.d.1.1; 01.C.d.1.2; 01.C.d.1.3; 01.C.d.2.1; 01.C.d.2.2;       01.C.d.2.3;                                                                   01.C.d.3.1; 01.C.d.3.2; 01.C.d.3.3; 01.C.e.1.1; 01.C.e.1.2; 01.C.e.1.3;       01.C.e.2.1;                                                                   01.C.e.2.2; 01.C.e.2.3; 01.C.e.3.1; 01.C.e.3.2; 01.C.e.3.3; 01.C.f.1.1;       01.C.f.1.2;                                                                   01.C.f.1.3; 01.C.f.2.1; 01.C.f.2.2; 01.C.f.2.3; 01.C.f.3.1; 01.C.f.3.2;       01.C.f.3.3; 01.D.a.1.1;                                                       01.D.a.1.2; 01.D.a.1.3; 01.D.a.2.1; 01.D.a.2.2; 01.D.a.2.3; 01.D.a.3.1;       01.D.a.3.2;                                                                   01.D.a.3.3; 01.D.b.1.1; 01.D.b.1.2; 01.D.b.1.3; 01.D.b.2.1; 01.D.b.2.2;       01.D.b.2.3;                                                                   01.D.b.3.1; 01.D.b.3.2; 01.D.b.3.3; 01.D.c.1.1; 01.D.c.1.2; 01.D.c.1.3;       01.D.c.2.1;                                                                   01.D.c.2.2; 01.D.c.2.3; 01.D.c.3.1; 01.D.c.3.2; 01.D.c.3.3; 01.D.d.1.1;       01.D.d.1.2;                                                                   01.D.d.1.3; 01.D.d.2.1; 01.D.d.2.2; 01.D.d.2.3; 01.D.d.3.1; 01.D.d.3.2;       01.D.d.3.3;                                                                   01.D.e.1.1; 01.D.e.1.2; 01.D.e.1.3; 01.D.e.2.1; 01.D.e.2.2; 01.D.e.2.3;       01.D.e.3.1;                                                                   01.D.e.3.2; 01.D.e.3.3; 01.D.f.1.1; 01.D.f.1.2; 01.D.f.1.3; 01.D.f.2.1;       01.D.f.2.2;                                                                   01.D.f.2.3; 01.D.f.3.1; 01.D.f.3.2; 01.D.f.3.3; 02.A.a.1.1; 02.A.a.1.2;       02.A.a.1.3;                                                                   02.A.a.2.1; 02.A.a.2.2; 02.A.a.2.3; 02.A.a.3.1; 02.A.a.3.2; 02.A.a.3.3;       02.A.b.1.1;                                                                   02.A.b.1.2; 02.A.b.1.3; 02.A.b.2.1; 02.A.b.2.2; 02.A.b.2.3; 02.A.b.3.1;       02.A.b.3.2;                                                                   02.A.b.3.3; 02.A.c.1.1; 02.A.c.1.2; 02.A.c.1.3; 02.A.c.2.1; 02.A.c.2.2;       02.A.c.2.3;                                                                   02.A.c.3.1; 02.A.c.3.2; 02.A.c.3.3; 02.A.d.1.1; 02.A.d.1.2; 02.A.d.1.3;       02.A.d.2.1;                                                                   02.A.d.2.2; 02.A.d.2.3; 02.A.d.3.1; 02.A.d.3.2; 02.A.d.3.3; 02.A.e.1.1;       02.A.e.1.2;                                                                   02.A.e.1.3; 02.A.e.2.1; 02.A.e.2.2; 02.A.e.2.3; 02.A.e.3.1; 02.A.e.3.2;       02.A.e.3.3;                                                                   02.A.f.1.1; 02.A.f.1.2; 02.A.f.1.3; 02.A.f.2.1; 02.A.f.2.2; 02.A.f.2.3;       02.A.f.3.1;                                                                   02.A.f.3.2; 02.A.f.3.3; 02.B.a.I.1; 02.B.a.1.2; 02.B.a.1.3; 02.B.a.2.1;       02.B.a.2.2;                                                                   02.B.a.2.3; 02.B.a.3.1; 02.B.a.3.2; 02.B.a.3.3; 02.B.b.1.1; 02.B.b.1.2;       02.B.b.1.3;                                                                   02.B.b.2.1; 02.B.b.2.2; 02.B.b.2.3; 02.B.b.3.1; 02.B.b.3.2; 02.B.b.3.3;       02.B.c.1.1;                                                                   02.B.c.1.2; 02.B.c.1.3; 02.B.c.2.1; 02.B.c.2.2; 02.B.c.2.3; 02.B.c.3.1;       02.B.c.3.2;                                                                   02.B.c.3.3; 02.B.d.1.1; 02.B.d.1.2; 02.B.d.1.3; 02.B.d.2.1; 02.B.d.2.2;       02.B.d.2.3;                                                                   02.B.d.3.1; 02.B.d.3.2; 02.B.d.3.3; 02.B.e.1.1; 02.B.e.1.2; 02.B.e.1.3;       02.B.e.2.1;                                                                   02.B.e.2.2; 02.B.e.2.3; 02.B.e.3.1; 02.B.e.3.2; 02.B.e.3.3; 02.B.f.1.1;       02.B.f.1.2;                                                                   02.B.f.1.3; 02.B.f.2.1; 02.B.f.2.2; 02.B.f.2.3; 02.B.f.3.1; 02.B.f.3.2;       02.B.f.3.3; 02.C.a.1.1;                                                       02.C.a.1.2; 02.C.a.1.3; 02.C.a.2.1; 02.C.a.2.2; 02.C.a.2.3; 02.C.a.3.1;       02.C.a.3.2;                                                                   02.C.a.3.3; 02.C.b.1.1; 02.C.b.1.2; 02.C.b.1.3; 02.C.b.2.1; 02.C.b.2.2;       02.C.b.2.3;                                                                   02.C.b.3.1; 02.C.b.3.2; 02.C.b.3.3; 02.C.c.1.1; 02.C.c.1.2; 02.C.c.1.3;       02.C.c.2.1;                                                                   02.C.c.2.2; 02.C.c.2.3; 02.C.c.3.1; 02.C.c.3.2; 02.C.c.3.3; 02.C.d.1.1;       02.C.d.1.2;                                                                   02.C.d,1.3; 02.C.d.2.1; 02.C.d.2.2; 02.C.d.2.3; 02.C.d.3.1; 02.C.d.3.2;       02.C.d.3.3;                                                                   02.C.e.1.1; 02.C.e.1.2; 02.C.e.1.3; 02.C.e.2.1; 02.C.e.2.2; 02.C.e.2.3;       02.C.e.3.1;                                                                   02.C.e.3.2; 02.C.e.3.3; 02.C.f.1.1; 02.C.f.1.2; 02.C.f.1.3; 02.C.f.2.1;       02.C.f.2.2;                                                                   02.C.f.2.3; 02.C.f.3.1; 02.C.f.3.2; 02.C.f.3.3; 02.D.a.1.1; 02.D.a.1.2;       02.D.a.1.3;                                                                   02.D.a.2.1; 02.D.a.2.2; 02.D.a.2.3; 02.D.a.3.1; 02.D.a.3.2; 02.D.a.3.3;       02.D.b.1.1;                                                                   02.D.b.1.2; 02.D.b.1.3; 02.D.b.2.1; 02.D.b.2.2; 02.D.b.2.3; 02.D.b.3.1;       02.D.b.3.2;                                                                   02.D.b.3.3; 02.D.c.1.1; 02.D.c.1.2; 02.D.c.1.3; 02.D.c.2.1; 02.D.c.2.2;       02.D.c.2.3;                                                                   02.D.c.3.1; 02.D.c.3.2; 02.D.c.3.3; 02.D.d.1.1; 02.D.d.1.2; 02.D.d.1.3;       02.D.d.2.1;                                                                   02.D.d.2.2; 02.D.d.2.3; 02.D.d.3.1; 02.D.d.3.2; 02.D.d.3.3; 02.D.e.1.1;       02.D.e.1.2;                                                                   02.D.e.1.3; 02.D.e.2.1; 02.D.e.2.2; 02.D.e.2.3; 02.D.e.3.1; 02.D.e.3.2;       02.D.e.3.3;                                                                   02.D.f.1.1; 02.D.f.1.2; 02.D.f.1.3; 02.D.f.2.1; 02.D.f.2.2; 02.D.f.2.3;       02.D.f.3.1;                                                                   02.D.f.3.2; 02.D.f.3.3; 03.A.a.1.1; 03.A.a.1.2; 03.A.a.1.3; 03.A.a.2.1;       03.A.a.2.2;                                                                   03.A.a.2.3; 03.A.a.3.1; 03.A.a.3.2; 03.A.a.3.3; 03.A.b.1.1; 03.A.b.1.2;       03.A.b.1.3;                                                                   03.A.b.2.1; 03.A.b.2.2; 03.A.b.2.3; 03.A.b.3.1; 03.A.b.3.2; 03.A.b.3.3;       03.A.c.1.1;                                                                   03.A.c.1.2; 03.A.c.1.3; 03.A.c.2.1; 03.A.c.2.2; 03.A.c.2.3; 03.A.c.3.1;       03.A.c.3.2;                                                                   03.A.c.3.3; 03.A.d.1.1; 03.A.d.1.2; 03.A.d.1.3; 03.A.d.2.1; 03.A.d.2.2;       03.A.d.2.3;                                                                   03.A.d.3.1; 03.A.d.3.2; 03.A.d.3.3; 03.A.e.1.1; 03.A.e.1.2; 03.A.e.1.3;       03.A.e.2.1;                                                                   03.A.e.2.2; 03.A.e.2.3; 03.A.e.3.1; 03.A.e.3.2; 03.A.e.3.3; 03.A.f.1.1;       03.A.f.1.2;                                                                   03.A.f.1.3; 03.A.f.2.1; 03.A.f.2.2; 03.A.f.2.3; 03.A.f.3.1; 03.A.f.3.2;       03.A.f.3.3;                                                                   03.B.a.1.1; 03.B.a.1.2; 03.B.a.1.3; 03.B.a.2.1; 03.B.a.2.2; 03.B.a.2.3;       03.B.a.3.1;                                                                   03.B.a.3.2; 03.B.a.3.3; 03.B.b.1.1; 03.B.b.1.2; 03.B.b.1.3; 03.B.b.2.1;       03.B.b.2.2;                                                                   03.B.b.2.3; 03.B.b.3.1; 03.B.b.3.2; 03.B.b.3.3; 03.B.c.1.1; 03.B.c.1.2;       03.B.c.1.3;                                                                   03.B.c.2.1; 03.B.c.2.2; 03.B.c.2.3; 03.B.c.3.1; 03.B.c.3.2; 03.B.c.3.3;       03.B.d.1.1;                                                                   03.B.d.1.2; 03.B.d.1.3; 03.B.d.2.1; 03.B.d.2.2; 03.B.d.2.3; 03.B.d.3.1;       03.B.d.3.2;                                                                   03.B.d.3,3; 03.B.e.1.1; 03.B.e.1.2; 03.B.e.1.3; 03.B.e.2.1; 03.B.e.2.2;       03.B.e.2.3;                                                                   03.B.e.3.1; 03.B.e.3.2; 03.B.e.3.3; 03.B.f.1.1; 03.B.f.1.2; 03.B.f.1.3;       03.B.f.2.1;                                                                   03.B.f.2.2; 03.B.f.2.3; 03.B.f.3.1; 03.B.f.3.2; 03.B.f.3.3; 03.C.a.1.1;       03.C.a.1.2;                                                                   03.C.a.1.3; 03.C.a.2.1; 03.C.a.2.2; 03.C.a.2.3; 03.C.a.3.1; 03.C.a.3.2;       03.C.a.3.3;                                                                   03.C.b.1.1; 03.C.b.1.2; 03.C.b.1.3; 03.C.b.2.1; 03.C.b.2.2; 03.C.b.2.3;       03.C.b.3.1;                                                                   03.C.b.3.2; 03.C.b.3.3; 03.C.c.1.1; 03.C.c.I.2; 03.C.c.1.3; 03.C.c.2.1;       03.C.c.2.2;                                                                   03.C.c.2,3; 03.C.c.3.1; 03.C.c.3.2; 03.C.c.3.3; 03.C.d.1.1; 03.C.d.1.2;       03.C.d.1.3;                                                                   03.C.d.2.1; 03.C.d.2.2; 03.C.d.2.3; 03.C.d.3.1; 03.C.d.3.2; 03.C.d.3.3;       03.C.e.1.1;                                                                   03.C.e.1.2; 03.C.e.1.3; 03.C.e.2.1; 03.C.e.2.2; 03.C.e.2.3; 03.C.e.3.1;       03.C.e.3.2;                                                                   03.C.e.3.3; 03.C.f.1.1; 03.C.f.1.2; 03.C.f.1.3; 03.C.f.2.1; 03.C.f.2.2;       03.C.f.2.3; 03.C.f.3.1;                                                       03.C.f.3.2; 03.C.f.3.3; 03.D.a.1.1; 03.D.a.1.2; 03.D.a.1.3; 03.D.a.2.1;       03.D.a.2.2;                                                                   03.D.a.2.3; 03.D.a.3.1; 03.D.a.3.2; 03.D.a.3.3; 03.D.b.1.1; 03.D.b.1.2;       03.D.b.1.3;                                                                   03.D.b.2.1; 03.D.b.2.2; 03.D.b.2.3; 03.D.b.3.1; 03.D.b.3.2; 03.D.b.3.3;       03.D.c.1.1;                                                                   03.D.c.1.2; 03.D.c.1.3; 03.D.c.2.1; 03.D.c.2.2; 03.D.c.2.3; 03.D.c.3.1;       03.D.c.3.2;                                                                   03.D.c.3.3; 03.D.d.1.1; 03.D.d.1.2; 03.D.d.1.3; 03.D.d.2.1; 03.D.d.2.2;       03.D.d.2.3;                                                                   03.D.d.3.1; 03.D.d.3.2; 03.D.d.3.3; 03.D.e.1.1; 03.D.e.1.2; 03.D.e.1.3;       03.D.e.2.1;                                                                   03.D.e.2.2; 03.D.e.2.3; 03.D.e.3.1; 03.D.e.3.2; 03.D.e.3.3; 03.D.f.1.1;       03.D.f.1.2;                                                                   03.D.f.1.3; 03.D.f.2.1; 03.D.f.2.2; 03.D.f.2.3; 03.D.f.3.1; 03.D.f.3.2;       03.D.f.3.3;                                                                   04.A.a.1.1; 04.A.a.1.2; 04.A.a.1.3; 04.A.a.2.1; 04.A.a.2.2; 04.A.a.2.3;       04.A.a.3.1;                                                                   04.A.a.3.2; 04.A.a.3.3; 04.A.b.1.1; 04.A.b.1.2; 04.A.b.1.3; 04.A.b.2.1;       04.A.b.2.2;                                                                   04.A.b.2.3; 04.A.b.3.1; 04.A.b.3.2; 04.A.b.3.3; 04.A.c.1.1; 04.A.c.1.2;       04.A.c.1.3;                                                                   04.A.c.2.1; 04.A.c.2.2; 04.A.c.2.3; 04.A.c.3.1; 04.A.c.3.2; 04.A.c.3.3;       04.A.d.1.1;                                                                   04.A.d.1.2; 04.A.d.1.3; 04.A.d.2.1; 04.A.d.2.2; 04.A.d.2.3; 04.A.d.3.1;       04.A.d.3.2;                                                                   04.A.d.3.3; 04.A.e.1.1; 04.A.e.1.2; 04.A.e.1.3; 04.A.e.2.1; D4.A.e.2.2;       04.A.e.2.3;                                                                   04.A.e.3.1; 04.A.e.3.2; 04.A.e.3.3; 04.A.f.1.1; 04.A.f.1.2; 04.A.f.1.3;       04.A.f.2.1;                                                                   04.A.f.2.2; 04.A.f.2.3; 04.A.f.3.1; 04.A.f.3.2; 04.A.f.3.3; 04.B.a.1.1;       04.B.a.1.2;                                                                   04.B.a.1.3; 04.B.a.2.1; 04.B.a.2.2; 04.B.a.2.3; 04.B.a.3.1; 04.B.a.3.2;       04.B.a.3.3;                                                                   04.B.b.1.1; 04.B.b.1.2; 04.B.b.1.3; 04.B.b.2.1; 04.B.b.2.2; 04.B.b.2.3;       04.B.b.3.1;                                                                   04.B.b.3.2; 04.B.b.3.3; 04.B.c.1.1; 04.B.c.1.2; 04.B.c.1.3; 04.B.c.2.1;       04.B.c.2.2;                                                                   04.B.c.2.3; 04.B.c.3.1; 04.B.c.3.2; 04.B.c.3.3; 04.B.d.1.1; 04.B.d.1.2;       04.B.d.1.3;                                                                   04.B.d.2.1; 04.B.d.2.2; 04.B.d.2.3; 04.B.d.3.1; 04.B.d.3.2; 04.B.d.3.3;       04.B.e.1.1;                                                                   04.B.e.1.2; 04.B.e.1.3; 04.B.e.2.1; 04.B.e.2.2; 04.B.e.2.3; 04.B.e.3.1;       04.B.e.3.2;                                                                   04.B.e.3.3; 04.B.f.1.1; 04.B.f.1.2; 04.B.f.1.3; 04.B.f.2.1; 04.B.f.2.2;       04.B.f.2.3; 04.B.f.3.1;                                                       04.B.f.3.2; 04.B.f.3.3; 04.C.a.1.1; 04.C.a.1.2; 04.C.a.1.3; 04.C.a.2.1;       04.C.a.2.2;                                                                   04.C.a.2.3; 04.C.a.3.1; 04.C.a.3.2; 04.C.a.3.3; 04.C.b.1.1; 04.C.b.1.2;       04.C.b.1.3;                                                                   04.C.b.2.1; 04.C.b.2.2; 04.C.b.2.3; 04.C.b.3.1; 04.C.b.3.2; 04.C.b.3.3;       04.C.c.1.1;                                                                   04.C.c.1.2; 04.C.c.1.3; 04.C.c.2.1; 04.C.c.2.2; 04.C.c.2.3; 04.C.c.3.1;       04.C.c.3.2;                                                                   04.C.c.3.3; 04.C.d.1.1; 04.C.d.1.2; 04.C.d.1.3; 04.C.d.2.1; 04.C.d.2.2;       04.C.d.2.3;                                                                   04.C.d.3.1; 04.C.d.3.2; 04.C.d.3.3; 04.C.e.1.1; 04.C.e.1.2; 04.C.e.1.3;       04.C.e.2.1;                                                                   04.C.e.2.2; 04.C.e.2.3; 04.C.e.3.1; 04.C.e.3.2; 04.C.e.3.3; 04.C.f.1.1;       04.C.f.1.2;                                                                   04.C.f.1.3; 04.C.f.2.1; 04.C.f.2.2; 04.C.f.2.3; 04.C.f.3.1; 04.C.f.3.2;       04.C.f.3.3; 04.D.a.1.1;                                                       04.D.a.1.2; 04.D.a.1.3; 04.D.a.2.1; 04.D.a.2.2; 04.D.a.2.3; 04.D.a.3.1;       04.D.a.3.2;                                                                   04.D.a.3.3; 04.D.b.1.1; 04.D.b.1.2; 04.D.b.1.3; 04.D.b.2.1; 04.D.b.2.2;       04.D.b.2.3;                                                                   04.D.b.3.1; 04.D.b.3.2; 04.D.b.3.3; 04.D.c.1.1; 04.D.c.1.2; 04.D.c.1.3;       04.D.c.2.1;                                                                   04.D.c.2.2; 04.D.c.2.3; 04.D.c.3.1; 04.D.c.3.2; 04.D.c.3.3; 04.D.d.1.1;       04.D.d.1.2;                                                                   04.D.d.1.3; 04.D.d.2.1; 04.D.d.2.2; 04.D.d.2.3; 04.D.d.3.1; 04.D.d.3.2;       04.D.d.3.3;                                                                   04.D.e.1.1; 04.D.e.1.2; 04.D.e.1.3; 04.D.e.2.1; 04.D.e.2.2; 04.D.e.2.3;       04.D.e.3.1;                                                                   04.D.e.3.2; 04.D.e.3.3; 04.D.f.1.1; 04.D.f.1.2; 04.D.f.1.3; 04.D.f.2.1;       04.D.f.2.2;                                                                   04.D.f.2.3; 04.D.f.3.1; 04.D.f.3.2; 04.D.f.3.3; 18.A.a.1.1; 18.A.a.1.2;       18.A.a.1.3;                                                                   18.A.a.2.1; 18.A.a.2.2; 18.A.a.2.3; 18.A.a.3.1; 18.A.a.3.2; 18.A.a.3.3;       18.A.b.1.1;                                                                   18.A.b.1.2; 18.A.b.1.3; 18.A.b.2.1; 18.A.b.2.2; 18.A.b.2.3; 18.A.b.3.1;       18.A.b.3.2;                                                                   18.A.b.3.3; 18.A.c.1.1; 18.A.c.1.2; 18.A.c.1.3; 18.A.c.2.1; 18.A.c.2.2;       18.A.c.2.3;                                                                   18.A.c.3.1; 18.A.c.3.2; 18.A.c.3.3; 18.A.d.1.1; 18.A.d.1.2; 18.A.d.1.3;       18.A.d.2.1;                                                                   18.A.d.2.2; 18.A.d.2.3; 18.A.d.3.1; 18.A.d.3.2; 18.A.d.3.3; 18.A.e.1.1;       18.A.e.1.2;                                                                   18.A.e.1.3; 18.A.e.2.1; 18.A.e.2.2; 18.A.e.2.3; 18.A.e.3.1; 18.A.e.3.2;       18.A.e.3.3;                                                                   18.A.f.1.1; 18.A.f.1.2; 18.A.f.1.3; 18.A.f.2.1; 18.A.f.2.2; 18.A.f.2.3;       18.A.f.3.1;                                                                   18.A.f.3.2; 18.A.f.3.3; 18.B.a.1.1; 18.B.a.1.2; 18.B.a.1.3; 18.B.a.2.1;       18.B.a.2.2;                                                                   18.B.a.2.3; 18.B.a.3.1; 18.B.a.3.2; 18.B.a.3.3; 18.B.b.1.1; 18.B.b.1.2;       18.B.b.1.3;                                                                   18.B.b.2.1; 18.B.b.2.2; 18.B.b.2.3; 18.B.b.3.1; 18.B.b.3.2; 18.B.b.3.3;       18.B.c.1.1;                                                                   18.B.c.1.2; 18.B.c.1.3; 18.B.c.2.1; 18.B.c.2.2; 18.B.c.2.3; 18.B.c.3.1;       18.B.c.3.2;                                                                   18.B.c.3.3; 18.B.d.1.1; 18.B.d.1.2; 18.B.d.1.3; 18.B.d.2.1; 18.B.d.2.2;       18.B.d.2.3;                                                                   18.B.d.3.1; 18.B.d.3.2; 18.B.d.3.3; 18.B.e.1.1; 18.B.e.1.2; 18.B.e.1.3;       18.B.e.2.1;                                                                   18.B.e.2.2; 18.B.e.2.3; 18.B.e.3.1; 18.B.e.3.2; 18.B.e.3.3; 18.B.f.1.1;       18.B.f.1.2;                                                                   18.B.f.1.3; 18.B.f.2.1; 18.B.f.2.2; 18.B.f.2.3; 18.B.f.3.1; 18.B.f.3.2;       18.B.f.3.3; 18.C.a.1.1;                                                       18.C.a.1.2; 18.C.a.1.3; 18.C.a.2.1; 18.C.a.2.2; 18.C.a.2.3; 18.C.a.3.1;       18.C.a.3.2;                                                                   18.C.a.3.3; 18.C.b.1.1; 18.C.b.1.2; 18.C.b.1.3; 18.C.b.2.1; 18.C.b.2.2;       18.C.b.2.3;                                                                   18.C.b.3.1; 18.C.b.3.2; 18.C.b.3.3; 18.C.c.1.1; 18.C.c.1.2; 18.C.c.1.3;       18.C.c.2.1;                                                                   18.C.c.2.2; 18.C.c.2.3; 18.C.c.3.1; 18.C.c.3.2; 18.C.c.3.3; 18.C.d.1.1;       18.C.d.1.2;                                                                   18.C.d.1.3; 18.C.d.2.1; 18.C.d.2.2; 18.C.d.2.3; 18.C.d.3.1; 18.C.d.3.2;       18.C.d.3.3;                                                                   18.C.e.1.1; 18.C.e.1.2; 18.C.e.1.3; 18.C.e.2.1; 18.C.e.2.2; 18.C.e.2.3;       18.C.e.3.1;                                                                   18.C.e.3.2; 18.C.e.3.3; 18.C.f.1.1; 18.C.f.1.2; 18.C.f.1.3; 18.C.f.2.1;       18.C.f.2.2;                                                                   18.C.f.2.3; 18.C.f.3.1; 18.C.f.3.2; 18.C.f.3.3; 18.D.a.1.1; 18.D.a.1.2;       18.D.a.1.3;                                                                   18.D.a.2.1; 18.D.a.2.2; 18.D.a.2.3; 18.D.a.3.1; 18.D.a.3.2; 18.D.a.3.3;       18.D.b.1.1;                                                                   18.D.b.1.2; 18.D.b.1.3; 18.D.b.2.1; 18.D.b.2.2; 18.D.b.2.3; 18.D.b.3.1;       18.D.b.3.2;                                                                   18.D.b.3.3; 18.D.c.1.1; 18.D.c.1.2; 18.D.c.1.3; 18.D.c.2.1; 18.D.c.2.2;       18.D.c.2.3;                                                                   18.D.c.3.1; 18.D.c.3.2; 18.D.c.3.3; 18.D.d.1.1; 18.D.d.1.2; 18.D.d.1.3;       18.D.d.2.1;                                                                   18.D.d.2.2; 18.D.d.2.3; 18.D.d.3.1; 18.D.d.3.2; 18.D.d.3.3; 18.D.e.1.1;       18.D.e.1.2;                                                                   18.D.e.1.3; 18.D.e.2.1; 18.D.e.2.2; 18.D.e.2.3; 18.D.e.3.1; 18.D.e.3.2;       18.D.e.3.3;                                                                   18.D.f.1.1; 18.D.f.1.2; 18.D.f.1.3; 18.D.f.2.1; 18.D.f.2.2; 18.D.f.2.3;       18.D.f.3.1;                                                                   18.D.f.3.2; 18.D.f.3.3; 27.A.a.1.1; 27.A.a.1.2; 27.A.a.1.3; 27.A.a.2.1;       27.A.a.2.2;                                                                   27.A.a.2.3; 27.A.a.3.1; 27.A.a.3.2; 27.A.a.3.3; 27.A.b.1.1; 27.A.b.1.2;       27.A.b.1.3;                                                                   27.A.b.2.1; 27.A.b.2.2; 27.A.b.2.3; 27.A.b.3.1; 27.A.b.3.2; 27.A.b.3.3;       27.A.c.1.1;                                                                   27.A.c.1.2; 27.A.c.1.3; 27.A.c.2.1; 27.A.c.2.2; 27.A.c.2.3; 27.A.c.3.1;       27.A.c.3.2;                                                                   27.A.c.3.3; 27.A.d.1.1; 27.A.d.1.2; 27.A.d.1.3; 27.A.d.2.1; 27.A.d.2.2;       27.A.d.2.3;                                                                   27.A.d.3.1; 27.A.d.3.2; 27.A.d.3.3; 27.A.e.1.1; 27.A.e.1.2; 27.A.e.1.3;       27.A.e.2.1;                                                                   27.A.e.2.2; 27.A.e.2.3; 27.A.e.3.1; 27.A.e.3.2; 27.A.e.3.3; 27.A.f.1.1;       27.A.f.1.2;                                                                   27.A.f.1.3; 27.A.f.2.1; 27.A.f.2.2; 27.A.f.2.3; 27.A.f.3.1; 27.A.f.3.2;       27.A.f.3.3;                                                                   27.B.a.1.1; 27.B.a.1.2; 27.B.a.1.3; 27.B.a.2.1; 27.B.a.2.2; 27.B.a.2.3;       27.B.a.3.1;                                                                   27.B.a.3.2; 27.B.a.3.3; 27.B.b.1.1; 27.B.b.1.2; 27.B.b.1.3; 27.B.b.2.1;       27.B.b.2.2;                                                                   27.B.b.2.3; 27.B.b.3.1; 27.B.b.3.2; 27.B.b.3.3; 27.B.c.1.1; 27.B.c.1.2;       27.B.c.1.3;                                                                   27.B.c.2.1; 27.B.c.2.2; 27.B.c.2.3; 27.B.c.3.1; 27.B.c.3.2; 27.B.c.3.3;       27.B.d.1.1;                                                                   27.B.d.1.2; 27.B.d.1.3; 27.B.d.2.1; 27.B.d.2.2; 27.B.d.2.3; 27.B.d.3.1;       27.B.d.3.2;                                                                   27.B.d.3.3; 27.B.e.1.1; 27.B.e.1.2; 27.B.e.1.3; 27.B.e.2.1; 27.B.e.2.2;       27.B.e.2.3;                                                                   27.B.e.3.1; 27.B.e.3.2; 27.B.e.3.3; 27.B.f.1.1; 27.B.f.1.2; 27.B.f.1.3;       27.B.f.2.1;                                                                   27.B.f.2.2; 27.B.f.2.3; 27.B.f.3.1; 27.B.f.3.2; 27.B.f.3.3; 27.C.a.1.1;       27.C.a.1.2;                                                                   27.C.a.1.3; 27.C.a.2.1; 27.C.a.2.2; 27.C.a.2.3; 27.C.a.3.1; 27.C.a.3.2;       27.C.a.3.3;                                                                   27.C.b.1.1; 27.C.b.1.2; 27.C.b.1.3; 27.C.b.2.1; 27.C.b.2.2; 27.C.b.2.3;       27.C.b.3.1;                                                                   27.C.b.3.2; 27.C.b.3.3; 27.C.c.1.1; 27.C.c.1.2; 27.C.c.1.3; 27.C.c.2.1;       27.C.c.2.2;                                                                   27.C.c.2.3; 27.C.c.3.1; 27.C.c.3.2; 27.C.c.3.3; 27.C.d.1.1; 27.C.d.1.2;       27.C.d.1.3;                                                                   27.C.d.2.1; 27.C.d.2.2; 27.C.d.2.3; 27.C.d.3.1; 27.C.d.3.2; 27.C.d.3.3;       27.C.e.1.1;                                                                   27.C.e.1.2; 27.C.e.1.3; 27.C.e.2.1; 27.C.e.2.2; 27.C.e.2.3; 27.C.e.3.1;       27.C.e.3.2;                                                                   27.C.e.3.3; 27.C.f.1.1; 27.C.f.1.2; 27.C.f.1.3; 27.C.f.2.1; 27.C.f.2.2;       27.C.f.2.3; 27.C.f.3.1;                                                       27.C.f.3.2; 27.C.f.3.3; 27.D.a.1.1; 27.D.a:1.2; 27.D.a.1.3; 27.D.a.2.1;       27.D.a.2.2;                                                                   27.D.a.2.3; 27.D.a.3.1; 27.D.a.3.2; 27.D.a.3.3; 27.D.b.1.1; 27.D.b.1.2;       27.D.b.1.3;                                                                   27.D.b.2.1; 27.D.b.2.2; 27.D.b.2.3; 27.D.b.3.1; 27.D.b.3.2; 27.D.b.3.3;       27.D.c.1.1;                                                                   27.D.c.1.2; 27.D.c.1.3; 27.D.c.2.1; 27.D.c.2.2; 27.D.c.2.3; 27.D.c.3.1;       27.D.c.3.2;                                                                   27.D.c.3.3; 27.D.d.1.1; 27.D.d.1.2; 27.D.d.1.3; 27.D.d.2.1; 27.D.d.2.2;       27.D.d.2.3;                                                                   27.D.d.3.1; 27.D.d.3.2; 27.0.d.3.3; 27.D.e.1.1; 27.D.e.1.2; 27.D.e.1.3;       27.D.e.2.1;                                                                   27.D.e.2.2; 27.D.e.2.3; 27.D.e.3.1; 27.D.e.3.2; 27.D.e.3.3; 27.D.f.1.1;       27.D.f.1.2;                                                                   27.D.f.1.3; 27.D.f.2.1; 27.D.f.2.2; 27.D.f.2.3; 27.D.f.3.1; 27.D.f.3.2;       27.D.f.3.3;                                                                   28.A.a.1.1; 28.A.a.1.2; 28.A.a.1.3; 28.A.a.2.1; 28.A.a.2.2; 28.A.a.2.3;       28.A.a.3.1;                                                                   28.A.a.3.2; 28.A.a.3.3; 28:A.b.1.1; 28.A.b.1.2; 28.A.b.1.3; 28.A.b.2.1;       28.A.b.2.2;                                                                   28.A.b.2.3; 28.A.b.3.1; 28.A.b.3.2; 28.A.b.3.3; 28.A.c.1.1; 28.A.c.1.2;       28.A.c.1.3;                                                                   28.A.c.2.1; 28.A.c.2.2; 28.A.c.2.3; 28.A.c.3.1; 28.A.c.3.2; 28.A.c.3.3;       28.A.d.1.1;                                                                   28.A.d.1.2; 28.A.d.1.3; 28.A.d.2.1; 28.A.d.2.2; 28.A.d.2.3; 28.A.d.3.1;       28.A.d.3.2;                                                                   28.A.d.3.3; 28.A.e.1.1; 28.A.e.1.2; 28.A.e.1.3; 28.A.e.2.1; 28.A.e.2.2;       28.A.e.2.3;                                                                   28.A.e.3.1; 28.A.e.3.2;.28.A.e.3.3; 28.A.f.1.1; 28.A.f.1.2; 28.A.f.1.3;       28.A.f.2.1;                                                                   28.A.f.2.2; 28.A.f.2.3; 28.A.f.3.1; 28.A.f.3.2; 28.A.f.3.3; 28.B.a.1.1;       28.B.a.1.2;                                                                   28.B.a.1.3; 28.B.a.2.1; 28.B.a.2.2; 28.B.a.2.3; 28.B.a.3.1; 28.B.a.3.2;       28.B.a.3.3;                                                                   28.B.b.1.1; 28.B.b.1.2; 28.B.b.1.3; 28.B.b.2.1; 28.B.b.2.2; 28.B.b.2.3;       28.B.b.3.1;                                                                   28.B.b.3.2; 28.B.b.3.3; 28.B.c.1.1; 28.B.c.1.2; 28.B.c.1.3; 28.B.c.2.1;       28.B.c.2.2;                                                                   28.B.c.2.3; 28.B.c.3.1; 28.B.c.3.2; 28.B.c.3.3; 28.B.d.1.1; 28.B.d.1.2;       28.B.d.1.3;                                                                   28.B.d.2.1; 28.B.d.2.2; 28.B.d.2.3; 28.B.d.3.1; 28.B.d.3.2; 28.B.d.3.3;       28.B.e.1.1;                                                                   28.B.e.1.2; 28.B.e.1.3; 28.B.e.2.1; 28.B.e.2.2; 28.B.e.2.3; 28.B.e.3.1;       28.B.e.3.2,                                                                   28.B.e.3.3; 28.B.f.1.1; 28.B.f.1.2; 28.B.f.1.3; 28.B.f.2.1; 28.B.f.2.2;       28.B.f.2.3; 28.B.f.3.1;                                                       28.B.f.3.2; 28.B.f.3.3; 28.C.a.1.1; 28.C.a.1.2; 28.C.a.1.3; 28.C.a.2.1;       28.C.a.2.2;                                                                   28.C.a.2.3; 28.C.a.3.1; 28.C.a.3.2; 28.C.a.3.3; 28.C.b.1.1; 28.C.b.1.2;       28.C.b.1.3;                                                                   28.C.b.2.1; 28.C.b.2.2; 28.C.b.2.3; 28.C.b.3.1; 28.C.b.3.2; 28.C.b.3.3;       28.C.c.1.1;                                                                   28.C.c.1.2; 28.C.c.1.3; 28.C.c.2.1; 28.C.c.2.2; 28.C.c.2.3; 28.C.c.3.1;       28.C.c.3.2;                                                                   28.C.c.3.3; 28.C.d.1.1; 28.C.d.1.2; 28.C.d.1.3; 28.C.4.2.1; 28.C.d.2.2;       28.C.d.2.3;                                                                   28.C.d.3.1; 28.C.d.3.2; 28.C.d.3.3; 28.C.e.1.1; 28.C.e.1.2; 28.C.e.1.3;       28.C.e.2.1;                                                                   28.C.e.2.2; 28.C.e.2.3; 28.C.e.3.1; 28.C.e.3.2; 28.C.e.3.3; 28.C.f.1.1;       28.C.f.1.2;                                                                   28.C.f.1.3; 28.C.f.2.1; 28.C.f.2.2; 28.C.f.2.3; 28.C.f.3.1; 28.C.f.3.2;       28.C.f.3.3; 28.D.a.1.1;                                                       28.D.a.1.2; 28.D.a.1.3; 28.D.a.2.1; 28.D.a.2.2; 28.D.a.2.3; 28.D.a.3.1;       28.D.a.3.2;                                                                   28.D.a.3.3; 28.D.b.1.1; 28.D.b.1.2; 28.D.b.1.3; 28.D.b.2.1; 28.D.b.2.2;       28.D.b.2.3;                                                                   28.D.b.3.1; 28.D.b.3.2; 28.D.b.3.3; 28.D.c.1.1; 28.D.c.1.2; 28.D.c.1.3;       28.D.c.2.1;                                                                   28.D.c.2.2; 28.D.c.2.3; 28.D.c.3.1; 28.D.c.3.2; 28.D.c.3.3; 28.D.d.1.1;       28.D.d.1.2;                                                                   28.D.d.1.3; 28.D.d.2.1; 28.D.d.2.2; 28.D.d.2.3; 28.D.d.3.1; 28.D.d.3.2;       28.D.d.3.3;                                                                   28.D.e.1.1; 28.D.e.1.2; 28.D.e.1.3; 28.D.e.2.1; 28.D.e.2.2; 28.D.e.2.3;       28.D.e.3.1;                                                                   28.D.e.3.2; 28.D.e.3.3; 28.D.f.1.1; 28.D.f.1.2; 28.D.f.1.3; 28.D.f.2.1;       28.D.f.2.2;                                                                   28.D.f.2.3; 28.D.f.3.1; 28.D.f.3.2; 28.D.f.3.3; 29.A.a.1.1; 29.A.a.1.2;       29.A.a.1.3;                                                                   29.A.a.2.1; 29.A.a.2.2; 29.A.a.2.3; 29.A.a.3.1; 29.A.a.3.2; 29.A.a.3.3;       29.A.b.1.1;                                                                   29.A.b.1.2; 29.A.b.1.3; 29.A.b.2.1; 29.A.b.2.2; 29.A.b.2.3;                   29.A.b.3.1;.29.A.b.3.2;                                                       29.A.b.3.3; 29.A.c.1.1; 29.A.c.1.2; 29.A.c.1.3; 29.A.c.2.1; 29.A.c.2.2;       29.A.c.2.3;                                                                   29.A.c.3.1; 29.A.c.3.2; 29.A.c.3.3; 29.A.d.1.1; 29.A.d.1.2; 29.A.d.1.3;       29.A.d.2.1;                                                                   29.A.d.2.2;.29.A.d.2.3; 29.A.d.3.1; 29.A.d.3.2; 29.A.d.3.3; 29.A.e.1.1;       29.A.e.1.2;                                                                   29.A.e.1.3; 29.A.e.2.1; 29.A.e.2.2; 29.A.e.2.3; 29.A.e.3.1; 29.A.e.3.2;       29.A.e.3.3;                                                                   29.A.f.1.1; 29.A.f.1.2; 29.A.f.1.3; 29.A.f.2.1; 29.A.f.2.2; 29.A.f.2.3;       29.A.f.3.1;                                                                   29.A.f.3.2; 29.A.f.3.3; 29.B.a.1.1; 29.B.a.1.2; 29.B.a.1.3;                   29.B.a.2.1;.29.B.a.2.2;                                                       29.B.a.2.3; 29.B.a.3.1; 29.B.a.3.2; 29.B.a.3.3; 29.B.b.1.1; 29.B.b.1.2;       29.B.b.1.3;                                                                   29.B.b.2.1; 29.B.b.2.2; 29.B.b.2.3; 29.B.b.3.1; 29.B.b.3.2; 29.B.b.3.3;       29.B.c.1.1;                                                                   29.B.c.1.2; 29.B.c.1.3; 29.B.c.2.1; 29.B.c.2.2; 29.B.c.2.3; 29.B.c.3.1;       29.B.c.3.2;                                                                   29.B.c.3.3; 29.B.d.1.1; 29.B.d.1.2; 29.B.d.1.3; 29.B.d.2.1; 29.B.d.2.2;       29.B.d.2.3;                                                                   29.B.d.3.1; 29.B.d.3.2; 29.B.d.3.3; 29.B.e.1.1; 29.B.e.1.2; 29.B.e.1.3;       29.B.e.2.1;                                                                   29.B.e.2.2; 29.B.e.2.3; 29.B.e.3.1; 29.B.e.3.2; 29.B.e.3.3; 29.B.f.1.1;       29.B.f.1.2;                                                                   29.B.f.1.3; 29.B.f.2.1; 29.B.f.2.2; 29.B.f.2.3; 29.B.f.3.1; 29.B.f.3.2;       29.B.f.3.3; 29.C.a.1.1;                                                       29.C.a.1.2; 29.C.a.1.3; 29.C.a.2.1; 29.C.a.2.2; 29.C.a.2.3; 29.C.a.3.1;       29.C.a.3.2;                                                                   29.C.a.3.3; 29.C.b.1.1; 29.C.b.1.2; 29.C.b.1.3; 29.C.b.2.1; 29.C.b.2.2;       29.C.b.2.3;                                                                   29.C.b.3.1; 29.C.b.3.2; 29.C.b.3.3; 29.C.c.1.1; 29.C.c.1.2; 29.C.c.1.3;       29.C.c.2.1;                                                                   29.C.c.2.2; 29.C.c.2.3; 29.C.c.3.1; 29.C.c.3.2; 29.C.c.3.3; 29.C.d.1.1;       29.C.d.1.2;                                                                   29.C.d.1.3; 29.C.d.2.1; 29.C.d.2.2; 29.C.d.2.3; 29.C.d.3.1; 29.C.d.3.2;       29.C.d.3.3;                                                                   29.C.e.1.1; 29.C.e.1.2; 29.C.e.1.3; 29.C.e.2.1; 29.C.e.2.2; 29.C.e.2.3;       29.C.e.3.1;                                                                   29.C.e.3.2; 29.C.e.3.3; 29.C.f.1.1; 29.C.f.1.2; 29.C.f.1.3; 29.C.f.2.1;       29.C.f.2.2;                                                                   29.C.f.2.3; 29.C.f.3.1; 29.C.f.3.2; 29.C.f.3.3; 29.D.a.1.1; 29.D.a.1.2;       29.D.a.1.3;                                                                   29.D.a.2.1; 29.D.a.2.2; 29.D.a.2.3; 29.D.a.3.1; 29.D.a.3.2; 29.D.a.3.3;       29.D.b.1.1;                                                                   29.D.b.1.2; 29.D.b.1.3; 29.D.b.2.1; 29.D.b.2.2; 29.D.b.2.3; 29.D.b.3.1;       29.D.b.3.2;                                                                   29.D.b.3.3; 29.D.c.1.1; 29.D.c.1.2; 29.D.c.1.3; 29.D.c.2.1; 29.D.c.2.2;       29.D.c.2.3;                                                                   29.D.c.3.1; 29.D.c.3.2; 29.D.c.3.3; 29.D.d.1.1; 29.D.d.1.2; 29.D.d.1.3;       29.D.d.2.1;                                                                   29.D.d.2.2; 29.D.d.2.3; 29.D.d.3.1; 29.D.d.3.2; 29.D.d.3.3; 29.D.e.1.1;       29.D.e.1.2;                                                                   29.D.e.1.3; 29.D.e.2.1; 29.D.e.2.2; 29.D.e.2.3; 29.D.e.3.1; 29.D.e.3.2;       29.D.e.3.3;                                                                   29.D.f.1.1; 29.D.f.1.2; 29.D.f.1.3; 29.D.f.2.1; 29.D.f.2.2; 29.D.f.2.3;       29.D.f.3.1;                                                                   29.D.f.3.2; 29.D.f.3.3; 30.A.a.1.1; 30.A.a.1.2; 30.A.a.1.3; 30.A.a.2.1;       30.A.a.2.2;                                                                   30.A.a.2.3; 30.A.a.3.1; 30.A.a.3.2; 30.A.a.3.3; 30.A.b.1.1; 30.A.b.1.2;       30.A.b.1.3;                                                                   30.A.b.2.1; 30.A.b.2.2; 30.A.b.2.3; 30.A.b.3.1; 30.A.b.3.2; 30.A.b.3.3;       30.A.c.1.1;                                                                   30.A.c.1.2; 30.A.c.1.3; 30.A.c.2.1; 30.A.c.2.2; 30.A.c.2.3; 30.A.c.3.1;       30.A.c.3.2;                                                                   30.A.c.3.3; 30.A.d.1.1; 30.A.d.1.2; 30.A.d.1.3; 30.A.d.2.1; 30.A.d.2.2;       30.A.d.2.3;                                                                   30.A.d.3.1; 30.A.d.3.2; 30.A.d.3.3; 30.A.e.1.1; 30.A.e.1.2; 30.A.e.1.3;       30.A.e.2.1;                                                                   30.A.e.2.2; 30.A.e.2.3, 30.A.e.3.1; 30.A.e.3.2; 30.A.e.3.3; 30.A.f.1.1;       30.A.f.1.2;                                                                   30.A.f.1.3; 30.A.f.2.1; 30.A.f.2.2; 30.A.f.2.3; 30.A.f.3.1; 30.A.f.3.2;       30.A.f.3.3;                                                                   30.B.a.1.1; 30.B.a.1.2; 30.B.a.1.3; 30.B.a.2.1; 30.B.a.2.2; 30.B.a.2.3;       30.B.a.3.1;                                                                   30.B.a.3.2; 30.B.a.3.3; 30.B.b.1.1; 30.B.b.1.2; 30.B.b.1.3; 30.B.b.2.1;       30.B.b.2.2;                                                                   30.B.b.2.3; 30.B.b.3.1; 30.B.b.3.2; 30.B.b.3.3; 30.B.c.1.1; 30.B.c.1.2;       30.B.c.1.3;                                                                   30.B.c.2.1; 30.B.c.2.2; 30.B.c.2.3; 30.B.c.3.1; 30.B.c.3.2; 30.B.c.3.3;       30.B.d.1.1;                                                                   30.B.d.1.2; 30.B.d.1.3; 30.B.d.2.1; 30.B.d.2.2; 30.B.d.2.3; 30.B.d.3.1;       30.B.d.3.2;                                                                   30.B.d.3.3; 30.B.e.1.1; 30.B.e.1.2; 30.B.e.1.3; 30.B.e.2.1; 30.B.e.2.2;       30.B.e.2.3;                                                                   30.B.e.3.1; 30.B.e.3.2; 30.B.e.3.3; 30.B.f.1.1; 30.B.f.1.2; 30.B.f.1.3;       30.B.f.2.1;                                                                   30.B.f.2.2; 30.B.f.2.3; 30.B.f.3.1; 30.B.f.3.2; 30.B.f.3.3; 30.C.a.1.1;       30.C.a.1.2;                                                                   30.C.a.1.3; 30.C.a.2.1; 30.C.a.2.2; 30.C.a.2.3; 30.C.a.3.1; 30.C.a.3.2;       30.C.a.3.3;                                                                   30.C.b.1.1; 30.C.b.1.2; 30.C.b.1.3; 30.C.b.2.1; 30.C.b.2.2; 30.C.b.2.3;       30.C.b.3.1;                                                                   30.C.b.3.2; 30.C.b.3.3; 30.C.c.1.1; 30.C.c.1.2; 30.C.c.1.3; 30.C.c.2.1;       30.C.c.2.2;                                                                   30.C.c.2.3; 30.C.c.3.1; 30.C.c.3.2; 30.C.c.3.3;.30.C.d.1.1; 30.C.d.1.2;       30.C.d.1.3;                                                                   30.C.d.2.1; 30.C.d.2.2; 30.C.d.2.3; 30.C.d.3.1; 30.C.d.3.2; 30.C.d.3.3;       30.C.e.1.1;                                                                   30.C.e.1.2; 30.C.e.1.3; 30.C.e.2.1; 30.C.e.2.2; 30.C.e.2.3; 30.C.e.3.1;       30.C.e.3.2;                                                                   30.C.e.3.3; 30.C.f.1.1; 30.C.f.1.2; 30.C.f.1.3; 30.C.f.2.1; 30.C.f.2.2;       30.C.f.2.3; 30.C.f.3.1;                                                       30.C.f.3.2; 30.C.f.3.3; 30.D.a.1.1; 30.D.a.1.2; 30.D.a.1.3; 30.D.a.2.1;       30.D.a.2.2;                                                                   30.D.a.2.3; 30.D.a.3.1; 30.D.a.3.2; 30.D.a.3.3; 30.D.b.4.1; 30.D.b.1.2;       30.D.b.1.3;                                                                   30.D.b.2.1; 30.D.b.2.2; 30.D.b.2.3; 30.D.b.3.1; 30.D.b.3.2; 30.D.b.3.3;       30.D.c.1.1;                                                                   30.D.c.1.2; 30.D.c.1.3; 30.D.c.2.1; 30.D.c.2.2; 30.D.c.2.3; 30.D.c.3.1;       30.D.c.3.2;                                                                   30.D.c.3.3;.30.D.d.1.1; 30.D.d.1.2; 30.D.d.1.3; 30.D.d.2.1; 30.D.d.2.2;       30.D.d.2.3;                                                                   30.D.d.3.1; 30.D.d.3.2; 30.D.d.3.3; 30.D.e.1.1; 30.D.e.1.2; 30.D.e.1.3;       30.D.e.2.1;                                                                   30.D.e.2.2; 30.D.e.2.3; 30.D.e.3.1; 30.D.e.3.2; 30.D.e.3.3; 30.D.f.1.1;       30.D.f.1.2;                                                                   30.D.f.1.3; 30.D.f.2.1; 30.D.f.2.2; 30.D.f.2.3; 30.D.f.3.1; 30.D.f.3.2;       30.D.f.3.3;                                                                   31.A.a.1.1; 31.A.a.1.2; 31.A.a.1.3; 31.A.a.2.1; 31.A.a.2.2; 31.A.a.2.3;       31.A.a.3.1;                                                                   31.A.a.3.2; 31.A.a.3.3; 31.A.b.1.1; 31.A.b.1.2; 31.A.b.1.3; 31.A.b.2.1;       31.A.b.2.2;                                                                   31.A.b.2.3; 31.A.b.3.1; 31.A.b.3.2; 31.A.b.3.3; 31.A.c.1.1; 31.A.c.1.2;       31.A.c.1.3;                                                                   31.A.c.2.1; 31.A.c.2.2; 31.A.c.2.3; 31.A.c.3.1; 31.A.c.3.2; 31.A.c.3.3;       31.A.d.1.1;                                                                   31.A.d.1.2; 31.A.d.1.3; 31.A.d.2.1; 31.A.d.2.2; 31.A.d.2.3; 31.A.d.3.1;       31.A.d.3.2;                                                                   31.A.d.3.3; 31.A.e.1.1; 31.A.e.1.2; 31.A.e.1.3; 31.A.e.2.1; 31.A.e.2.2;       31.A.e.2.3;                                                                   31.A.e.3.1; 31.A.e.3.2; 31.A.e.3.3; 31.A.f.1.1; 31.A.f.1.2; 31.A.f.1.3;       31.A.f.2.1;                                                                   31.A.f.2.2; 31.A.f.2.3; 31.A.f.3.1; 31.A.f.3.2; 31.A.f.3.3; 31.B.a.1.1;       31.B.a.1.2;                                                                   31.B.a.1.3; 31.B.a.2.1; 31.B.a.2.2; 31.B.a.2.3; 31.B.a.3.1; 31.B.a.3.2;       31.B.a.3.3;                                                                   31.B.b.1.1; 31.B.b.1.2; 31.B.b.1.3; 31.B.b.2.1; 31.B.b.2.2; 31.B.b.2.3;       31.B.b.3.1;                                                                   31.B.b.3.2; 31.B.b.3.3; 31.B.c.1.1; 31.B.c.1.2; 31.B.c.1.3; 31.B.c.2.1;       31.B.c.2.2;                                                                   31.B.c.2.3; 31.B.c.3.1; 31.B.c.3.2; 31.B.c.3.3; 31.B.d.1.1; 31.B.d.1.2;       31.B.d.1.3;                                                                   31.B.d.2.1; 31.B.d.2.2; 31.B.d.2.3; 31.B.d.3.1; 31.B.d.3.2; 31.B.d.3.3;       31.B.e.1.1;                                                                   31.B.e.1.2; 31.B.e.1.3; 31.B.e.2.1; 31.B.e.2.2; 31.B.e.2.3; 31.B.e.3.1;       31.B.e.3.2;                                                                   31.B.e.3.3; 31.B.f.1.1; 31.B.f.1.2; 31.B.f.1.3; 31.B.f.2.1; 31.B.f.2.2;       31.B.f.2.3; 31.B.f.3.1;                                                       31.B.f.3.2; 31.B.f.3.3; 31.C.a.1.1; 31.C.a.1.2; 31.C.a.1.3; 31.C.a.2.1;       31.C.a.2.2;                                                                   31.C.a.2.3; 31.C.a.3.1; 31.C.a.3.2; 31.C.a.3.3; 31.C.b.1.1; 31.C.b.1.2;       31.C.b.1.3;                                                                   31.C.b.2.1; 31.C.b.2.2; 31.C.b.2.3; 31.C.b.3.1; 31.C.b.3.2; 31.C.b.3.3;       31.C.c.1.1;                                                                   31.C.c.1.2; 31.C.c.1.3; 31.C.c.2.1; 31.C.c.2.2; 31.C.c.2.3; 31.C.c.3.1;       31.C.c.3.2;                                                                   31.C.c.3.3; 31.C.d.1.1; 31.C.d.1.2; 31.C.d.1.3; 31.C.d.2.1; 31.C.d.2.2;       31.C.d.2.3;                                                                   31.C.d.3.1; 31.C.d.3.2; 31.C.d.3.3; 31.C.e.1.1; 31.C.e.1.2; 31.C.e.1.3;       31.C.e.2.1;                                                                   31.C.e.2.2; 31.C.e.2.3; 31.C.e.3.1; 31.C.e.3.2; 31.C.e.3.3; 31.C.f.1.1;       31.C.f.1.2;                                                                   31.C.f.1.3; 31.C.f.2.1; 31.C.f.2.2; 31.C.f.2.3; 31.C.f.3.1; 31.C.f.3.2;       31.C.f.3.3; 31.D.a.1.1;                                                       31.D.a.1.2; 31.D.a.1.3; 31.D.a.2.1; 31.D.a.2.2; 31.D.a.2.3; 31.D.a.3.1;       31.D.a.3.2;                                                                   31.D.a.3.3; 31.D.b.1.1; 31.D.b.1.2; 31.D.b.1.3; 31.D.b.2.1; 31.D.b.2.2;       31.D.b.2.3;                                                                   31.D.b.3.1; 31.D.b.3.2; 31.D.b.3.3; 31.D.c.1.1; 31.D.c.1.2; 31.D.c.1.3;       31.D.c.2.1;                                                                   31.D.c.2.2; 31.D.c.2.3; 31.D.c.3.1; 31.D.c.3.2; 31.D.c.3.3; 31.D.d.1.1;       31.D.d:1.2;                                                                   31.D.d.1.3; 31.D.d.2.1; 31.D.d.2.2; 31.D.d.2.3; 31.D.d.3.1; 31.D.d.3.2;       31.D.d.3.3;                                                                   31.D.e.1.1; 31.D.e.1.2; 31.D.e.1.3; 31.D.e.2.1; 31.D.e.2.2; 31.D.e.2.3;       31.D.e.3.1;                                                                   31.D.e.3.2; 31.D.e.3.3; 31.D.f.1.1; 31.D.f.1.2; 31.D.f.1.3; 31.D.f.2.1;       31.D.f.2.2;                                                                   31.D.f.2.3; 31.D.f.3.1; 31.D.f.3.2; 31.D.f.3.3; 32.A.a.1.1; 32.A.a.1.2;       32.A.a.1.3;                                                                   32.A.a.2.1; 32.A.a.2.2; 32.A.a.2.3; 32.A.a.3.1; 32.A.a.3.2; 32.A.a.3.3;       32.A.b.1.1;                                                                   32.A.b.1.2; 32.A.b.1.3; 32.A.b.2.1; 32.A.b.2.2; 32.A.b.2.3; 32.A.b.3.1;       32.A.b.3.2;                                                                   32.A.b.3.3; 32.A.c.1.1; 32.A.c.1.2; 32.A.c.1.3; 32.A.c.2.1; 32.A.c.2.2;       32.A.c.2.3;                                                                   32.A.c.3.1; 32.A.c.3.2; 32.A.c.3.3; 32.A.d.1.1; 32.A.d.1.2; 32.A.d.1.3;       32.A.d.2.1;                                                                   32.A.d.2.2; 32.A.d.2.3; 32.A.d.3.1; 32.A.d.3.2; 32.A.d.3.3; 32.A.e.1.1;       32.A.e.1.2;                                                                   32.A.e.1.3; 32.A.e.2.1; 32.A.e.2.2; 32.A.e.2.3; 32.A.e.3.1; 32.A.e.3.2;       32.A.e.3.3;                                                                   32.A.f.1.1; 32.A.f.1.2; 32.A.f.1.3; 32.A.f.2.1; 32.A.f.2.2; 32.A.f.2.3;       32.A.f.3.1;                                                                   32.A.f.3.2; 32.A.f.3.3; 32.B.a.1.1; 32.B.a.1.2; 32.B.a.1.3; 32.B.a.2.1;       32.B.a.2.2;                                                                   32.B.a.2.3; 32.B.a.3.1; 32.B.a.3.2; 32.B.a.3.3; 32.B.b.1.1; 32.B.b.1.2;       32.B.b.1.3;                                                                   32.B.b.2.1; 32.B.b.2.2; 32.B.b.2.3; 32.B.b.3.1; 32.B.b.3.2; 32.B.b.3.3;       32.B.c.1.1;                                                                   32.B.c.1.2; 32.B.c.1.3; 32.B.c.2.1; 32.B.c.2.2; 32.B.c.2.3; 32.B.c.3.1;       32.B.c.3.2;                                                                   32.B.c.3.3; 32.B.d.1.1; 32.B.d.1.2; 32.B.d.1.3; 32.B.d.2.1; 32.B.d.2.2;       32.B.d.2.3;                                                                   32.B.d.3.1; 32.B.d.3.2; 32.B.d.3.3; 32.B.e.1.1; 32.B.e.1.2; 32.B.e.1.3;       32.B.e.2.1;                                                                   32.B.e.2.2; 32.B.e.2.3; 32.B.e.3.1; 32.B.e.3.2; 32.B.e.3.3; 32.B.f.1.1;       32.B.f.1.2;                                                                   32.B.f.1.3; 32.B.f.2.1; 32.B.f.2.2; 32.B.f.2.3; 32.B.f.3.1; 32.B.f.3.2;       32.B.f.3.3; 32.C.a.1.1;                                                       32.C.a.1.2; 32.C.a.1.3; 32.C.a.2.1; 32.C.a.2.2; 32.C.a.2.3; 32.C.a.3.1;       32.C.a.3.2;                                                                   32.C.a.3.3; 32.C.b.1.1; 32.C.b.1.2; 32.C.b.1.3; 32.C.b.2.1; 32.C.b.2.2;       32.C.b.2.3;                                                                   32.C.b.3.1; 32.C.b.3.2; 32.C.b.3.3; 32.C.c.1.1; 32.C.c.1.2; 32.C.c.1.3;       32.C.c.2.1;                                                                   32.C.c.2.2; 32.C.c.2.3; 32.C.c.3.1; 32.C.c.3.2; 32.C.c.3.3; 32.C.d.1.1;       32.C.d.1.2;                                                                   32.C.d.1.3; 32.C.d.2.1; 32.C.d.2.2; 32.C.d.2.3; 32.C.d.3.1; 32.C.d.3.2;       32.C.d.3.3;                                                                   32.C.e.1.1; 32.C.e.1.2; 32.C.e.1.3; 32.C.e.2.1; 32.C.e.2.2; 32.C.e.2.3;       32.C.e.3.1;                                                                   32.C.e.3.2; 32.C.e.3.3; 32.C.f.1.1; 32.C.f.1.2; 32.C.f.1.3; 32.C.f.2.1;       32.C.f.2.2;                                                                   32.C.f.2.3; 32.C.f.3.1; 32.C.f.3.2; 32.C.f.3.3; 32.D.a.1.1; 32.D.a.1.2;       32.D.a.1.3;                                                                   32.D.a.2.1; 32.D.a.2.2; 32.D.a.2.3; 32.D.a.3.1; 32.D.a.3.2; 32.D.a.3.3;       32.D.b.1.1;                                                                   32.D.b.1.2; 32.D.b.1.3; 32.D.b.2.1; 32.D.b.2.2; 32.D.b.2.3; 32.D.b.3.1;       32.D.b.3.2;                                                                   32.D.b.3.3; 32.D.c.1.1; 32.D.c.1.2; 32.D.c.1.3; 32.D.c.2.1; 32.D.c.2.2;       32.D.c.2.3;                                                                   32.D.c.3.1; 32.D.c.3.2; 32.D.c.3.3; 32.D.d.1.1; 32.D.d.1.2; 32.D.d.1.3;       32.D.d.2.1;                                                                   32.D.d.2.2; 32.D.d.2.3; 32.D.d.3.1; 32.D.d.3.2; 32.D.d.3.3; 32.D.e.1.1;       32.D.e.1.2;                                                                   32.D.e.1.3; 32.D.e.2.1; 32.D.e.2.2; 32.D.e.2.3; 32.D.e.3.1; 32.D.e.3.2;       32.D.e.3.3;                                                                   32:D.f.1.1; 32.D.f.1.2; 32.D.f.1.3; 32.D.f 2.1; 32.D.f.2.2; 32.D.f.2.3;       32.D.f.3.1;                                                                   32.D.f.3.2; 32.D.f.3.3; 33.A.a.1.1; 33.A.a.1.2; 33.A.a.1.3; 33.A.a.2.1;       33.A.a.2.2;                                                                   33.A.a.2.3; 33.A.a.3.1; 33.A.a.3.2; 33.A.a.3.3; 33.A.b.1.1; 33.A.b.1.2;       33.A.b.1.3;                                                                   33.A.b.2.1; 33.A.b.2.2; 33.A.b.2.3; 33.A.b.3.1; 33.A.b.3.2; 33.A.b.3.3;       33.A.c.1.1;                                                                   33.A.c.1.2; 33.A.c.1.3; 33.A.c.2.1; 33.A.c.2.2; 33.A.c.2.3; 33.A.c.3.1;       33.A.c.3.2;                                                                   33.A.c.3.3; 33.A.d.1.1; 33.A.d.1.2; 33.A.d.1.3; 33.A.d.2.1; 33.A.d.2.2;       33.A.d.2.3;                                                                   33.A.d.3.1; 33.A.d.3.2; 33.A.d.3.3; 33.A.e.1.1; 33.A.e.1.2; 33.A.e.1.3;       33.A.e.2.1;                                                                   33.A.e.2.2; 33.A.e.2.3; 33.A.e.3.1; 33.A.e.3.2; 33.A.e.3.3; 33.A.f.1.1;       33.A.f.1.2;                                                                   33.A.f.1.3; 33.A.f.2.1; 33.A.f.2.2; 33.A.f.2.3; 33.A.f.3.1; 33.A.f.3.2;       33.A.f.3.3;                                                                   33.B.a.1.1; 33.B.a.1.2; 33.B.a.1.3; 33.B.a.2.1; 33.B.a.2.2; 33.B.a.2.3;       33.B.a.3.1;                                                                   33.B.a.3.2; 33.B.a.3.3; 33.B.b.1.1; 33.B.b.1.2; 33.B.b.1.3; 33.B.b.2.1;       33.B.b.2.2;                                                                   33.B.b.2.3; 33.B.b.3.1; 33.B.b.3.2; 33.B.b.3.3; 33.B.c.1.1; 33.B.c.1.2;       33.B.c.1.3;                                                                   33.B.c.2.1; 33.B.c.2.2; 33.B.c.2.3; 33.B.c.3.1; 33.B.c.3.2; 33.B.c.3.3;       33.B.d.1.1;                                                                   33.B.d.1.2; 33.B.d.1.3; 33.B.d.2.1; 33.B.d.2.2; 33.B.d.2.3; 33.B.d.3.1;       33.B.d.3.2;                                                                   33.B.d.3.3; 33.B.e.1.1; 33.B.e.1.2; 33.B.e.1.3; 33.B.e.2.1; 33.B.e.2.2;       33.B.e.2.3;                                                                   33.B.e.3.1; 33.B.e.3.2; 33.B.e.3.3; 33.B.f.1.1; 33.B.f.1.2; 33.B.f.1.3;       33.B.f.2.1;                                                                   33.B.f.2.2; 33.B.f.2.3; 33.B.f.3.1; 33.B.f.3.2; 33.B.f.3.3; 33.C.a.1.1;       33.C.a.1.2;                                                                   33.C.a.1.3; 33.C.a.2.1; 33.C.a.2.2; 33.C.a.2.3; 33.C.a.3.1; 33.C.a.3.2;       33.C.a.3.3;                                                                   33.C.b.1.1; 33.C.b.1.2; 33.C.b.1.3; 33.C.b.2.1; 33.C.b.2.2; 33.C.b.2.3;       33.C.b.3.1;                                                                   33.C.b.3.2; 33.C.b.3.3; 33.C.c.1.1; 33.C.c.1.2; 33.C.c.1.3; 33.C.c.2.1;       33.C.c.2.2;                                                                   33.C.c.2.3; 33.C.c.3.1; 33.C.c.3.2; 33.C.c.3.3; 33.C.d.1.1; 33.C.d.1.2;       33.C.d.1.3;                                                                   33.C.d.2.1; 33.C.d.2.2; 33.C.d.2.3; 33.C.d.3.1; 33.C.d.3.2; 33.C.d.3.3;       33.C.e.1.1;                                                                   33.C.e.1.2; 33.C.e.1.3; 33.C.e.2.1; 33.C.e.2.2; 33.C.e.2.3; 33.C.e.3.1;       33.C.e.3.2;                                                                   33.C.e.3.3; 33.C.f.1.1; 33.C.f.1.2; 33.C.f.1.3; 33.C.f.2.1;                   33.C.f.2.2;.33.C.f.2.3; 33.C.f.3.1;                                           33.C.f.3.2; 33.C.f.3.3; 33.D.a.1.1; 33.D.a.1.2; 33.D.a.1.3; 33.D.a.2.1;       33.D.a.2.2;                                                                   33.D.a.2.3; 33.D.a.3.1; 33.D.a.3.2; 33.D.a.3.3; 33.D.b.1.1; 33.D.b.1.2;       33.D.b.1.3;                                                                   33.D.b.2.1; 33.D.b.2.2; 33.D.b.2.3; 33.D.b.3.1;.33.D.b.3.2; 33.D.b.3.3;       33.D.c.1.1;                                                                   33.D.c.1.2; 33.D.c.1.3; 33.D.c.2.1; 33.D.c.2.2; 33.D.c.2.3; 33.D.c.3.1;       33.D.c.3.2;                                                                   33.D.c.3.3; 33.D.d.1.1; 33.D.d.1.2; 33.D.d.1.3; 33.D.d.2.1; 33.D.d.2.2;       33.D.d.2.3;                                                                   33.D.d.3.1; 33.D.d.3.2; 33.D.d.3.3; 33.D.e.1.1; 33.D.e.1.2; 33.D.e.1.3;       33.D.e.2.1;                                                                   33.D.e.2.2; 33.D.e.2.3; 33.D.e.3.1; 33.D.e.3.2; 33.D.e.3.3; 33.D.f.1.1;       33.D.f.1.2;                                                                   33.D.f.1.3; 33.D.f.2.1; 33.D.f.2.2; 33.D.f.2.3; 33.D.f.3.1; 33.D.f.3.2;       33.D.f.3.3;                                                                   34.A.a.1.1; 34.A.a.1.2; 34.A.a.1.3; 34.A.a.2.1; 34.A.a.2.2; 34.A.a.2.3;       34.A.a.3.1;                                                                   34.A.a.3.2; 34.A.a.3.3; 34.A.b.1.1; 34.A.b.1.2; 34.A.b.1.3; 34.A.b.2.1;       34.A.b.2.2;                                                                   34.A.b.2.3; 34.A.b.3.1; 34.A.b.3.2; 34.A.b.3.3; 34.A.c.1.1; 34.A.c.1.2;       34.A.c.1.3;                                                                   34.A.c.2.1; 34.A.c.2.2; 34.A.c.2.3; 34.A.c.3.1; 34.A.c.3.2; 34.A.c.3.3;       34.A.d.1.1;                                                                   34.A.d.1.2; 34.A.d.1.3; 34.A.d.2.1; 34.A.d.2.2; 34.A.d.2.3; 34.A.d.3.1;       34.A.d.3.2;                                                                   34.A.d.3.3; 34.A.e.1.1; 34.A.e.1.2; 34.A.e.1.3; 34.A.e.2.1; 34.A.e.2.2;       34.A.e.2.3;                                                                   34.A.e.3.1; 34.A.e.3.2; 34.A.e.3.3; 34.A.f.1.1; 34.A.f.1.2; 34.A.f.1.3;       34.A.f.2.1;                                                                   34.A.f.2.2; 34.A.f.2.3; 34.A.f.3.1; 34.A.f.3.2; 34.A.f.3.3; 34.B.a.1.1;       34.B.a.1.2;                                                                   34.B.a.1.3; 34.B.a.2.1; 34.B.a.2.2; 34.B.a.2.3; 34.B.a.3.1; 34.B.a.3.2;       34.B.a.3.3;                                                                   34.B.b.1.1; 34.B.b.1.2; 34.B.b.1.3; 34.B.b.2.1; 34.B.b.2.2; 34.B.b.2.3;       34.B.b.3.1;                                                                   34.B.b.3.2; 34.B.b.3.3; 34.B.c.1.1; 34.B.c.1.2; 34.B.c.1.3; 34.B.c.2.1;       34.B.c.2.2;                                                                   34.B.c.2.3; 34.B.c.3.1; 34.B.c.3.2; 34.B.c.3.3; 34.B.d.1.1; 34.B.d.1.2;       34.B.d.1.3;                                                                   34.B.d.2.1; 34.B.d.2.2; 34.B.d.2.3; 34.B.d.3.1; 34.B.d.3.2; 34.B.d.3.3;       34.B.e.1.1;                                                                   34.B.e.1.2; 34.B.e.1.3; 34.B.e.2.1; 34.B.e.2.2; 34.B.e.2.3; 34.B.e.3.1;       34.B.e.3.2;                                                                   34.B.e.3.3; 34.B.f.1.1; 34.B.f.1.2; 34.B.f.1.3; 34.B.f.2.1; 34.B.f.2.2;       34.B.f.2.3; 34.B.f.3.1;                                                       34.B.f.3.2; 34.B.f.3.3; 34.C.a.1.1; 34.C.a.1.2; 34.C.a.1.3; 34.C.a.2.1;       34.C.a.2.2;                                                                   34.C.a.2.3; 34.C.a.3.1; 34.C.a.3.2; 34.C.a.3.3; 34.C.b.1.1; 34.C.b.1.2;       34.C.b.1.3;                                                                   34.C.b.2.1; 34.C.b.2.2; 34.C.b.2.3; 34.C.b.3.1; 34.C.b.3.2; 34.C.b.3.3;       34.C.c.1.1;                                                                   34.C.c.1.2; 34.C.c.1.3; 34.C.c.2.1; 34.C.c.2.2; 34.C.c.2.3; 34.C.c.3.1;       34.C.c.3.2;                                                                   34.C.c.3.3; 34.C.d.1.1; 34.C.d.1.2; 34.C.d.1.3; 34.C.d.2.1; 34.C.d.2.2;       34.C.d.2.3;                                                                   34.C.d.3.1; 34.C.d.3.2; 34.C.d.3.3; 34.C.e.1.1; 34.C.e.1.2; 34.C.e.1.3;       34.C.e.2.1;                                                                   34.C.e.2.2; 34.C.e.2.3; 34.C.e.3.1; 34.C.e.3.2; 34.C.e.3.3; 34.C.f.1.1;       34.C.f.1.2;                                                                   34.C.f.1.3; 34.C.f.2.1; 34.C.f.2.2; 34.C.f.2.3; 34.C.f.3.1; 34.C.f.3.2;       34.C.f.3.3; 34.D.a.1.1;                                                       34.D.a.1.2; 34.D.a.1.3; 34.D.a.2.1; 34.D.a.2.2; 34.D.a.2.3; 34.D.a.3.1;       34.D.a.3.2;                                                                   34.D.a.3.3; 34.D.b.1.1; 34.D.b.1.2; 34.D.b.1.3; 34.D.b.2.1; 34.D.b.2.2;       34.D.b.2.3;                                                                   34.D.b.3.1; 34.D.b.3.2; 34.D.b.3.3; 34.D.c.1.1; 34.D.c.1.2; 34.D.c.1.3;       34.D.c.2.1;                                                                   34.D.c.2.2; 34.D.c.2.3; 34.D.c.3.1; 34.D.c.3.2; 34.D.c.3.3; 34.D.d.1.1;       34.D.d.1.2;                                                                   34.D.d.1.3; 34.D.d.2.1; 34.D.d.2.2; 34.D.d.2.3; 34.D.d.3.1; 34.D.d.3.2;       34.D.d.3.3;                                                                   34.D.e.1.1; 34.D.e.1.2; 34.D.e.1.3; 34.D.e.2.1; 34.D.e.2.2; 34.D.e.2.3;       34.D.e.3.1;                                                                   34.D.e.3.2; 34.D.e.3.3; 34.D.f.1.1; 34.D.f.1.2; 34.D.f.1.3; 34.D.f.2.1;       34.D.f.2.2;                                                                   34.D.f.2.3; 34.D.f.3.1; 34.D.f.3.2; 34.D.f.3.3.                               Key: Nucleus. Group Z. Group B. Group R.sup.1a.                               Furans                                                                        35.A.a.1; 35.A.a.2; 35.A.a.3; 35.A.b.1; 35.A.b.2; 35.A.b.3; 35.A.c.1;         35.A.c.2;                                                                     35.A.c.3; 35.A.d.1; 35.A.d.2; 35.A.d.3; 35.A.e.1; 35.A.e.2; 35.A.e.3;         35.A.f.1;                                                                     35.A.f.2; 35.A.f.3; 35.B.a.1; 35.B.a.2; 35.B.a.3; 35.B.b.1; 35.B.b.2;         35.B.b.3; 35.B.c.1;                                                           35.B.c.2; 35.B.c.3; 35.B.d.1; 35.B.d.2; 35.B.d.3; 35.B.e.1; 35.B.e.2;         35.B.e.3; 35.B.f.1;                                                           35.B.f.2; 35.B.f.3; 35.C.a.1; 35.C.a.2; 35.C.a.3; 35.C.b.1; 35.C.b.2;         35.C.b.3; 35.C.c.1;                                                           35.C.c.2; 35.C.c.3; 35.C.d.1; 35.C.d.2; 35.C.d.3; 35.C.e.1; 35.C.e.2;         35.C.e.3; 35.C.f.1;                                                           35.C.f.2; 35.C.f.3; 35.D.a.1; 35.D.a.2; 35.D.a.3; 35.D.b.1; 35.D.b.2;         35.D.b.3; 35.D.c.1;                                                           35.D.c.2; 35.D.c.3; 35.D.d.1; 35.D.d.2; 35.D.d.3; 35.D.e.1; 35.D.e.2;         35.D.e.3; 35.D.f.1;                                                           35.D.f.2; 35.D.f.3; 36.A.a.1; 36.A.a.2; 36.A.a.3; 36.A.b.1; 36.A.b.2;         36.A.b.3; 36.A.c.1;                                                           36.A.c.2; 36.A.c.3; 36.A.d.1; 36.A.d.2; 36.A.d.3; 36.A.e.1; 36.A.e.2;         36.A.e.3;                                                                     36.A.f.1; 36.A.f.2; 36.A.f.3; 36.B.a.1; 36.B.a.2; 36.B.a.3; 36.B.b.1;         36.B.b.2; 36.B.b.3;                                                           36.B.c.1; 36.B.c.2; 36.B.c.3; 36.B.d.1; 36.B.d.2; 36.B.d.3; 36.B.e.1;         36.B.e.2; 36.B.e.3;                                                           36.B.f.1; 36.B.f.2; 36.B.f.3; 36.C.a.1; 36.C.a.2; 36.C.a.3; 36.C.b.1;         36.C.b.2; 36.C.b.3;                                                           36.C.c.1; 36.C.c.2; 36.C.c.3; 36.C.d.1; 36.C.d.2; 36.C.d.3; 36.C.e.1;         36.C.e.2; 36.C.e.3;                                                           36.C.f.1; 36.C.f.2; 36.C.f.3; 36.D.a.1; 36.D.a.2; 36.D.a.3; 36.D.b.1;         36.D.b.2; 36.D.b.3;                                                           36.D.c.1; 36.D.c.2; 36.D.c.3; 36.D.d.1; 36.D.d.2; 36.D.d.3; 36.D.e.1;         36.D.e.2; 36.D.e.3;                                                           36.D.f.1; 36.D.f.2; 36.D.f.3; 37.A.a.1; 37.A.a.2; 37.A.a.3; 37.A.b.1;         37.A.b.2; 37.A.b.3;                                                           37.A.c.1; 37.A.c.2; 37.A.c.3; 37.A.d.1; 37.A.d.2; 37.A.d.3; 37.A.e.1;         37.A.e.2;                                                                     37.A.e.3; 37.A.f.1; 37.A.f.2; 37.A.f.3; 37.B.a.1; 37.B.a.2; 37.B.a.3;         37.B.b.1; 37.B.b.2;                                                           37.B.b.3; 37.B.c.1; 37.B.c.2; 37.B.c.3; 37.B.d.1; 37.B.d.2; 37.B.d.3;         37.B.e.1; 37.B.e.2;                                                           37.B.e.3; 37.B.f.1; 37.B.f.2; 37.B.f.3; 37.C.a.1; 37.C.a.2; 37.C.a.3;         37.C.b.1; 37.C.b.2;                                                           37.C.b.3; 37.C.c.1; 37.C.c.2; 37.C.c.3; 37.C.d.1; 37.C.d.2; 37.C.d.3;         37.C.e.1; 37.C.e.2;                                                           37.C.e.3; 37.C.f.1; 37.C.f.2; 37.C.f.3; 37.D.a.1; 37.D.a.2; 37.D.a.3;         37.D.b.1; 37.D.b.2;                                                           37.D.b.3; 37.D.c.1; 37.D.c.2; 37.D.c.3; 37.D.d.1; 37.D.d.2; 37.D.d.3;         37.D.e.1; 37.D.e.2;                                                           37.D.e.3; 37.D.f.1; 37.D.f.2; 37.D.f.3; 38.A.a.1; 38.A.a.2; 38.A.a.3;         38.A.b.1; 38.A.b.2;                                                           38.A.b.3; 38.A.c.1; 38.A.c.2; 38.A.c.3; 38.A.d.1; 38.A.d.2; 38.A.d.3;         38.A.e.1;                                                                     38.A.e.2; 38.A.e.3; 38.A.f.1; 38.A.f.2; 38.A.f.3; 38.B.a.1; 38.B.a.2;         38.B.a.3; 38.B.b.1;                                                           38.B.b.2; 38.B.b.3; 38.B.c.1; 38.B.c.2; 38.B.c.3; 38.B.d.1; 38.B.d.2;         38.B.d.3; 38.B.e.1;                                                           38.B.e.2; 38.B.e.3; 38.B.f.1; 38.B.f.2; 38.B.f.3; 38.C.a.1; 38.C.a.2;         38.C.a.3; 38.C.b.1;                                                           38.C.b.2; 38.C.b.3; 38.C.c.1; 38.C.c.2; 38.C.c.3; 38.C.d.1; 38.C.d.2;         38.C.d.3; 38.C.e.1;                                                           38.C.e.2; 38.C.e.3; 38.C.f.1; 38.C.f.2; 38.C.f.3; 38.D.a.1; 38.D.a.2;         38.D.a.3; 38.D.b.1;                                                           38.D.b.2; 38.D.b.3; 38.D.c.1; 38.D.c.2; 38.D.c.3; 38.D.d.1; 38.D.d.2;         38.D.d.3; 38.D.e.1;                                                           38.D.e.2; 38.D.e.3; 38.D.f.1; 38.D.f.2; 38.D.f.3; 39.A.a.1; 39.A.a.2;         39.A.a.3; 39.A.b.1;                                                           39.A.b.2; 39.A.b.3; 39.A.c.1; 39.A.c.2; 39.A.c.3; 39.A.d.1; 39.A.d.2;         39.A.d.3;                                                                     39.A.e.1; 39.A.e.2; 39.A.e.3; 39.A.f.1; 39.A.f.2; 39.A.f.3; 39.B.a.1;         39.B.a.2; 39.B.a.3;                                                           39.B.b.1; 39.B.b.2; 39.B.b.3; 39.B.c.1; 39.B.c.2; 39.B.c.3; 39.B.d.1;         39.B.d.2; 39.B.d.3;                                                           39.B.e.1; 39.B.e.2; 39.B.e.3; 39.B.f.1; 39.B.f.2; 39.B.f.3; 39.C.a.1;         39.C.a.2; 39.C.a.3;                                                           39.C.b.1; 39.C.b.2; 39.C.b.3; 39.C.c.1; 39.C.c.2; 39.C.c.3; 39.C.d.1;         39.C.d.2; 39.C.d.3;                                                           39.C.e.1; 39.C.e.2; 39.C.e.3; 39.C.f.1; 39.C.f.2; 39.C.f.3; 39.D.a.1;         39.D.a.2; 39.D.a.3;                                                           39.D.b.1; 39.D.b.2; 39.D.b.3; 39.D.c.1; 39.D.c.2; 39.D.c.3; 39.D.d.1;         39.D.d.2; 39.D.d.3;                                                           39.D.e.1; 39.D.e.2; 39.D.e.3; 39.D.f.1; 39.D.f.2; 39.D.f.3; 40.A.a.1;         40.A.a.2; 40.A.a.3;                                                           40.A.b.1; 40.A.b.2; 40.A.b.3; 40.A.c.1; 40.A.c.2; 40.A.c.3; 40.A.d.1;         40.A.d.2;                                                                     40.A.d.3; 40.A.e.1; 40.A.e.2; 40.A.e.3; 40.A.f.1; 40.A.f.2; 40.A.f.3;         40.B.a.1; 40.B.a.2;                                                           40.B.a.3; 40.B.b.1; 40.B.b.2; 40.B.b.3; 40.B.c.1; 40.B.c.2; 40.B.c.3;         40.B.d.1; 40.B.d.2;                                                           40.B.d.3; 40.B.e.1; 40.B.e.2; 40.B.e.3; 40.B.f.1; 40.B.f.2; 40.B.f.3;         40.C.a.1; 40.C.a.2;                                                           40.C.a.3; 40.C.b.1; 40.C.b.2; 40.C.b.3; 40.C.c.1; 40.C.c.2; 40.C.c.3;         40.C.d.1; 40.C.d.2;                                                           40.C.d.3; 40.C.e.1; 40.C.e.2; 40.C.e.3; 40.C.f.1; 40.C.f.2; 40.C.f.3;         40.D.a.1; 40.D.a.2;                                                           40.D.a.3; 40.D.b.1; 40.D.b.2; 40.D.b.3; 40.D.c.1; 40.D.c.2; 40.D.c.3;         40.D.d.1; 40.D.d.2;                                                           40.D.d.3; 40.D.e.1; 40.D.e.2; 40.D.e.3; 40.D.f.1; 40.D.f.2; 40.D.f.3;         41.A.a.1; 41.A.a.2;                                                           41.A.a.3; 41.A.b.1; 41.A.b.2; 41.A.b.3; 41.A.c.1; 41.A.c.2; 41.A.c.3;         41.A.d.1;                                                                     41.A.d.2; 41.A.d.3; 41.A.e.1; 41.A.e.2; 41.A.e.3; 41.A.f.1; 41.A.f.2;         41.A.f.3; 41.B.a.1;                                                           41.B.a.2; 41.B.a.3; 41.B.b.1; 41.B.b.2; 41.B.b.3; 41.B.c.1; 41.B.c.2;         41.B.c.3; 41.B.d.1;                                                           41.B.d.2; 41.B.d.3; 41.B.e.1; 41.B.e.2; 41.B.e.3; 41.B.f.1; 41.B.f.2;         41.B.f.3; 41.C.a.1;                                                           41.C.a.2; 41.C.a.3; 41.C.b.1; 41.C.b.2; 41.C.b.3; 41.C.c.1; 41.C.c.2;         41.C.c.3; 41.C.d.1;                                                           41.C.d.2; 41.C.d.3; 41.C.e.1; 41.C.e.2; 41.C.e.3; 41.C.f.1; 41.C.f.2;         41.C.f.3; 41.D.a.1;                                                           41.D.a.2; 41.D.a.3; 41.D.b.1; 41.D.b.2; 41.D.b.3; 41.D.c.1; 41.D.c.2;         41.D.c.3; 41.D.d.1;                                                           41.D.d.2; 41.D.d.3; 41.D.e.1; 41.D.e.2; 41.D.e.3; 41.D.f.1;.41.D.f.2;         41.D.f.3; 42.A.a.1;                                                           42.A.a.2; 42.A.a.3; 42.A.b.1; 42.A.b.2; 42.A.b.3; 42.A.c.1; 42.A.c.2;         42.A.c.3;                                                                     42.A.d.1; 42.A.d.2; 42.A.d.3; 42.A.e.1; 42.A.e.2; 42.A.e.3; 42.A.f.1;         42.A.f.2;                                                                     42.A.f.3; 42.B.a.1; 42.B.a.2; 42.B.a.3; 42.B.b.1; 42.B.b.2; 42.B.b.3;         42.B.c.1; 42.B.c.2;                                                           42.B.c.3; 42.B.d.1; 42.B.d.2; 42.B.d.3; 42.B.e.1; 42.B.e.2; 42.B.e.3;         42.B.f.1; 42.B.f.2;                                                           42.B.f.3; 42.C.a.1; 42.C.a.2; 42.C.a.3; 42.C.b.1; 42.C.b.2; 42.C.b.3;         42.C.c.1; 42.C.c.2;                                                           42.C.c.3; 42.C.d.1; 42.C.d.2; 42.C.d.3; 42.C.e.1; 42.C.e.2; 42.C.e.3;         42.C.f.1; 42.C.f.2;                                                           42.C.f.3; 42.D.a.1; 42.D.a.2; 42.D.a.3; 42.D.b.1; 42.D.b.2; 42.D.b.3;         42.D.c.1; 42.D.c.2;                                                           42.D.c.3; 42.D.d.1; 42.D.d.2; 42.D.d.3; 42.D.e.1; 42.D.e.2; 42.D.e.3;         42.D.f.1; 42.D.f.2;                                                           42.D.f.3; 43.A.a.1; 43.A.a.2; 43.A.a.3; 43.A.b.1; 43.A.b.2; 43.A.b.3;         43.A.c.1;                                                                     43.A.c.2; 43.A.c.3; 43.A.d.1; 43.A.d.2; 43.A.d.3; 43.A.e.1; 43.A.e.2;         43.A.e.3;                                                                     43.A.f.1; 43.A.f.2; 43.A.f.3; 43.B.a.1; 43.B.a.2; 43.B.a.3; 43.B.b.1;         43.B.b.2; 43.B.b.3;                                                           43.B.c.1; 43.B.c.2; 43.B.c.3; 43.B.d.1; 43.B.d.2; 43.B.d.3; 43.B.e.1;         43.B.e.2; 43.B.e.3;                                                           43.B.f.1; 43.B.f.2; 43.B.f.3; 43.C.a.1; 43.C.a.2; 43.C.a.3; 43.C.b.1;         43.C.b.2; 43.C.b.3;                                                           43.C.c.1; 43.C.c.2; 43.C.c.3; 43.C.d.1; 43.C.d.2; 43.C.d.3; 43.C.e.1;         43.C.e.2; 43.C.e.3;                                                           43.C.f.1; 43.C.f.2; 43.C.f.3; 43.D.a.1; 43.D.a.2; 43.D.a.3; 43.D.b.1;         43.D.b.2; 43.D.b.3;                                                           43.D.c.1; 43.D.c.2; 43.D.c.3; 43.D.d.1; 43.D.d.2; 43.D.d.3; 43.D.e.1;         43.D.e.2; 43.D.e.3;                                                           43.D.f.1; 43.D.f.2; 43.D.f.3.                                                 Key: Nucleus. Group Z. Group B. Group R.sup.1b.                               1-2 Unsaturated Pyrans                                                        19.A.a.1; 19.A.a.2; 19.A.a.3; 19.A.b.1; 19.A.b.2; 19.A.b.3; 19.A.c.1;         19.A.c.2;                                                                     19.A.c.3; 19.A.d.1; 19.A.d.2; 19.A.d.3; 19.A.e.1; 19.A.e.2; 19.A.e.3;         19.A.f.1;                                                                     19.A.f.2; 19.A.f.3; 19.B.a.1; 19.B.a.2; 19.B.a.3; 19.B.b.1; 19.B.b.2;         19.B.b.3; 19.B.c.1;                                                           19.B.c.2; 19.B.c.3; 19.B.d.1; 19.B.d.2; 19.B.d.3; 19.B.e.1; 19.B.e.2;         19.B.e.3; 19.B.f.1;                                                           19.B.f.2; 19.B.f.3; 19.C.a.1; 19.C.a.2; 19.C.a.3; 19.C.b.1; 19.C.b.2;         19.C.b.3; 19.C.c.1;                                                           19.C.c.2; 19.C.c.3; 19.C.d.1; 19.C.d.2; 19.C.d.3; 19.C.e.1; 19.C.e.2;         19.C.e.3; 19.C.f.1;                                                           19.C.f.2; 19.C.f.3; 19.D.a.1; 19.D.a.2; 19.D.a.3; 19.D.b.1; 19.D.b.2;         19.D.b.3; 19.D.c.1;                                                           19.D.c.2; 19.D.c.3; 19.D.d.1; 19.D.d.2; 19.D.d.3; 19.D.e.1; 19.D.e.2;         19.D.e.3; 19.D.f.1;                                                           19.D.f.2; 19.D.f.3; 20.A.a.1; 20.A.a.2; 20.A.a.3; 20.A.b.1; 20.A.b.2;         20.A.b.3; 20.A.c.1;                                                           20.A.c.2; 20.A.c.3; 20.A.d.1; 20.A.d.2; 20.A.d.3; 20.A.e.1; 20.A.e.2;         20.A.e.3;                                                                     20.A.f.1; 20.A.f.2; 20.A.f.3; 20.B.a.1; 20.B.a.2; 20.B.a.3; 20.B.b.1;         20.B.b.2; 20.B.b.3;                                                           20.B.c.1; 20.B.c.2; 20.B.c.3; 20.B.d.1; 20.B.d.2; 20.B.d.3; 20.B.e.1;         20.B.e.2; 20.B.e.3;                                                           20.B.f.1; 20.B.f.2; 20.B.f.3; 20.C.a.1; 20.C.a.2; 20.C.a.3; 20.C.b.1;         20.C.b.2; 20.C.b.3;                                                           20.C.c.1; 20.C.c.2; 20.C.c.3; 20.C.d.1; 20.C.d.2; 20.C.d.3; 20.C.e.1;         20.C.e.2; 20.C.e.3;                                                           20.C.f.1; 20.C.f.2; 20.C.f.3; 20.D.a.1; 20.D.a.2; 20.D.a.3; 20.D.b.1;         20.D.b.2; 20.D.b.3;                                                           20.D.c.1; 20.D.c.2; 20.D.c.3; 20.D.d.1; 20.D.d.2; 20.D.d.3; 20.D.e.1;         20.D.e.2; 20.D.e.3;                                                           20.D.f.1; 20.D.f.2; 20.D.f.3; 21.A.a.1; 21.A.a.2; 21.A.a.3; 21.A.b.1;         21.A.b.2; 21.A.b.3;                                                           21.A.c.1; 21.A.c.2; 21.A.c.3; 21.A.d.1; 21.A.d.2; 21.A.d.3; 21.A.e.1;         21.A.e.2;                                                                     21.A.e.3; 21.A.f.1; 21.A.f.2; 21.A.f.3; 21.B.a.1; 21.B.a.2; 21.B.a.3;         21.B.b.1; 21.B.b.2;                                                           21.B.b.3; 21.B.c.1; 21.B.c.2; 21.B.c.3; 21.B.d.1; 21.B.d.2; 21.B.d.3;         21.B.e.1; 21.B.e.2;                                                           21.B.e.3; 21.B.f.1; 21.B.f.2; 21.B.f.3; 21.C.a.1; 21.C.a.2; 21.C.a.3;         21.C.b.1; 21.C.b.2;                                                           21.C.b.3; 21.C.c.1; 21.C.c.2; 21.C.c.3; 21.C.d.1; 21.C.d.2; 21.C.d.3;         21.C.e.1; 21.C.e.2;                                                           21.C.e.3; 21.C.f.1; 21.C.f.2; 21.C.f.3; 21.D.a.1; 21.D.a.2; 21.D.a.3;         21.D.b.1; 21.D.b.2;                                                           21.D.b.3; 21.D.c.1; 21.D.c.2; 21.D.c.3; 21.D.d.1; 21.D.d.2; 21.D.d.3;         21.D.e.1; 21.D.e.2;                                                           21.D.e.3; 21.D.f.1; 21.D.f.2; 21.D.f.3; 22.A.a.1; 22.A.a.2; 22.A.a.3;         22.A.b.1; 22.A.b.2;                                                           22.A.b.3; 22.A.c.1; 22.A.c.2; 22.A.c.3; 22.A.d.1; 22.A.d.2;                   22.A.d.3;.22.A.e.1;                                                           22.A.e.2; 22.A.e.3; 22.A.f.1; 22.A.f.2; 22.A.f.3; 22.B.a.1; 22.B.a.2;         22.B.a.3; 22.B.b.1;                                                           22.B.b.2; 22.B.b.3; 22.B.c.1; 22.B.c.2; 22.B.c.3; 22.B.d.1; 22.B.d.2;         22.B.d.3; 22.B.e.1;                                                           22.B.e.2; 22.B.e.3; 22.B.f.1; 22.B.f.2; 22.B.f.3; 22.C.a.1; 22.C.a.2;         22.C.a.3; 22.C.b.1;                                                           22.C.b.2; 22.C.b.3; 22.C.c.1; 22.C.c.2; 22.C.c.3; 22.C.d.1; 22.C.d.2;         22.C.d.3; 22.C.e.1;                                                           22.C.e.2; 22.C.e.3; 22.C.f.1; 22.C.f.2; 22.C.f.3; 22.D.a.1; 22.D.a.2;         22.D.a.3; 22.D.b.1;                                                           22.D.b.2; 22.D.b.3; 22.D.c.1; 22.D.c.2; 22.D.c.3; 22.D.d.1; 22.D.d.2;         22.D.d.3; 22.D.e.1;                                                           22.D.e.2; 22.D.e.3; 22.D.f.1; 22.D.f.2; 22.D.f.3; 23.A.a.1; 23.A.a.2;         23.A.a.3; 23.A.b.1;                                                           23.A.b.2; 23.A.b.3; 23.A.c.1; 23.A.c.2; 23.A.c.3; 23.A.d.1; 23.A.d.2;         23.A.d.3;                                                                     23.A.e.1; 23.A.e.2; 23.A.e.3; 23.A.f.1; 23.A.f.2; 23.A.f.3; 23.B.a.1;         23.B.a.2; 23.B.a.3;                                                           23.B.b.1; 23.B.b.2; 23.B.b.3; 23.B.c.1; 23.B.c.2; 23.B.c.3; 23.B.d.1;         23.B.d.2; 23.B.d.3;                                                           23.B.e.1; 23.B.e.2; 23.B.e.3; 23.B.f.1; 23.B.f.2; 23.B.f.3; 23.C.a.1;         23.C.a.2; 23.C.a.3;                                                           23.C.b.1; 23.C.b.2; 23.C.b.3; 23.C.c.1; 23.C.c.2; 23.C.c.3; 23.C.d.1;         23.C.d.2; 23.C.d.3;                                                           23.C.e.1; 23.C.e.2; 23.C.e.3; 23.C.f.1; 23.C.f.2; 23.C.f.3; 23.D.a.1;         23.D.a.2; 23.D.a.3;                                                           23.D.b.1; 23.D.b.2; 23.D.b.3; 23.D.c.1; 23.D.c.2; 23.D.c.3; 23.D.d.1;         23.D.d.2; 23.D.d.3;                                                           23.D.e.1; 23.D.e.2; 23.D.e.3; 23.D.f.1; 23.D.f.2; 23.D.f.3; 24.A.a.1;         24.A.a.2; 24.A.a.3;                                                           24.A.b.1; 24.A.b.2; 24.A.b.3; 24.A.c.1; 24.A.c.2; 24.A.c.3; 24.A.d.1;         24.A.d.2;                                                                     24.A.d.3; 24.A.e.1; 24.A.e.2; 24.A.e.3; 24.A.f.1; 24.A.f.2; 24.A.f.3;         24.B.a.1; 24.B.a.2;                                                           24.B.a.3; 24.B.b.1; 24.B.b.2; 24.B.b.3; 24.B.c.1; 24.B.c.2; 24.B.c.3;         24.B.d.1; 24.B.d.2;                                                           24.B.d.3; 24.B.e.1; 24.B.e.2; 24.B.e.3; 24.B.f.1; 24.B.f.2; 24.B.f.3;         24.C.a.1; 24.C.a.2;                                                           24.C.a.3; 24.C.b.1; 24.C.b.2; 24.C.b.3; 24.C.c.1; 24.C.c.2; 24.C.c.3;         24.C.d.1;.24.C.d.2;                                                           24.C.d.3; 24.C.e.1; 24.C.e.2; 24.C.e.3; 24.C.f.1; 24.C.f.2; 24.C.f.3;         24.D.a.1;.24.D.d.2;                                                           24.D.a.3; 24.D.b.1; 24.D.b.2; 24.D.b.3; 24.D.c.1; 24.D.c.2; 24.D.c.3;         24.D.d.1; 24.D.d.2;                                                           24.D.d.3; 24.D.e.1; 24.D.e.2; 24.D.e.3; 24.D.f.1; 24.D.f.2; 24.D.f.3;         25.A.a.1; 25.A.a.2;                                                           25.A.a.3; 25.A.b.1; 25.A.b.2; 25.A.b.3; 25.A.c.1; 25.A.c.2; 25.A.c.3;         25.A.d.1;                                                                     25.A.d.2; 25.A.d.3; 25.A.e.1; 25.A.e.2; 25.A.e.3; 25.A.f.1; 25.A.f.2;         25.A.f.3; 25.B.a.1;                                                           25.B.a.2; 25.B.a.3; 25.B.b.1; 25.B.b.2; 25.B.b.3; 25.B.c.1; 25.B.c.2;         25.B.c.3; 25.B.d.1;                                                           25.B.d.2; 25.B.d.3; 25.B.e.1; 25.B.e.2; 25.B.e.3; 25.B.f.1; 25.B.f.2;         25.B.f.3; 25.C.a.1;                                                           25.C.a.2; 25.C.a.3; 25.C.b.1; 25.C.b.2; 25.C.b.3; 25.C.c.1; 25.C.c.2;         25.C.c.3; 25.C.d.1;                                                           25.C.d.2; 25.C.d.3; 25.C.e.1; 25.C.e.2; 25.C.e.3; 25.C.f.1; 25.C.f.2;         25.C.f.3; 25.D.a.1;                                                           25.D.a.2; 25.D.a.3; 25.D.b.1; 25.D.b.2; 25.D.b.3; 25.D.c.1; 25.D.c.2;         25.D.c.3; 25.D.d.1;                                                           25.D.d.2; 25.D.d.3; 25.D.e.1; 25.D.e.2; 25.D.e.3; 25.D.f.1; 25.D.f.2;         25.D.f.3; 26.A.a.1;                                                           26.A.a.2; 26.A.a.3; 26.A.b.1; 26.A.b.2; 26.A.b.3; 26.A.c.1; 26.A.c.2;         26.A.c.3;                                                                     26.A.d.1; 26.A.d.2; 26.A.d.3; 26.A.e.1; 26.A.e.2; 26.A.e.3; 26.A.f.1;         26.A.f.2;                                                                     26.A.f.3; 26.B.a.1; 26.B.a.2; 26.B.a.3; 26.B.b.1; 26.B.b.2; 26.B.b.3;         26.B.c.1; 26.B.c.2;                                                           26.B.c.3; 26.B.d.1; 26.B.d.2; 26.B.d.3; 26.B.e.1; 26.B.e.2; 26.B.e.3;         26.B.f.1; 26.B.f.2;                                                           26.B.f.3; 26.C.a.1; 26.C.a.2; 26.C.a.3; 26.C.b.1; 26.C.b.2;                   26.C.b.3;.26.C.c.1; 26.C.c.2;                                                 26.C.c.3; 26.C.d.1; 26.C.d.2; 26.C.d.3; 26.C.e.1; 26.C.e.2; 26.C.e.3;         26.C.f.1; 26.C.f.2;                                                           26.C.f.3; 26.D.a.1; 26.D.a.2; 26.D.a.3; 26:D.b.1; 26.D.b.2; 26.D.b.3;         26.D.c.1; 26.D.c.2;                                                           26.D.c.3; 26.D.d.1; 26.D.d.2; 26.D.d.3; 26.D.e.1; 26.D.e.2; 26.D.e.3;         26.D.f.1; 26.D.f.2;                                                           26.D.f.3.                                                                     Key: Nucleus. Group Z. Group B.                                               Fused Cyclopropyl and 2-3 Unsaturated Pyrans                                  05.A.a; 05.A.b; 05.A.c; 05.A.d; 05.A.e; 05.A.f; 05.B.a; 05.B.b; 05.B.c;       05.B.d; 05.B.e;                                                               05.B.f; 05.C.a; 05.C.b; 05.C.c; 05.C.d; 05.C.e; 05.C.f; 05.D.a; 05.D.b;       05.D.c; 05.D.d;                                                               05.D.e; 05.D.f; 06.A.a; 06.A.b; 06.A.c; 06.A.d; 06.A.e; 06.A.f; 06.B.a;       06.B.b; 06.B.c;                                                               06.B.d; 06.B.e; 06.B.f; 06.C.a; 06.C.b; 06.C.c; 06.C.d; 06.C.e; 06.C.f;       06.D.a; 06.D.b;                                                               06.D.c; 06.D.d; 06.D.e; 06.D.f; 07.A.a; 07.A.b; 07.A.c; 07.A.d; 07.A.e;       07.A.f; 07.B.a;                                                               07.B.b; 07.B.c; 07.B.d; 07.B.e; 07.B.f; 07.C.a; 07.C.b; 07.C.c; 07.C.d;       07.C.e; 07.C.f;                                                               07.D.a; 07.D.b; 07.D.c; 07.D.d; 07.D.e; 07.D.f; 08.A.a; 08.A.b; 08.A.c;       08.A.d; 08.A.e;                                                               08.A.f; 08.B.a; 08.B.b; 08.B.c; 08.B.d; 08.B.e; 08.B.f; 08.C.a; 08.C.b;       08.C.c; 08.C.d;                                                               08.C.e; 08.C.f; 08.D.a; 08.D.b; 08.D.c; 08.D.d; 08.D.e; 08.D.f; 09.A.a;       09.A.b; 09.A.c;                                                               09.A.d; 09.A.e; 09.A.f; 09.A.g; 09.A.h; 09.A.i; 09.A.j; 09.A.k; 09.A.l;       09.B.a; 09.B.b;                                                               09.B.c; 09.B.d; 09.B.e; 09.B.f; 09.B.g; 09.B.h; 09.B.i; 09.B.j; 09.B.k;       09.B.l; 09.C.a;                                                               09.C.b; 09.C.c; 09.C.d; 09.C.e; 09.C.f; 09.C.g; 09.C.h; 09:C.i; 09.C.j;       09.C.k; 09.C.l;                                                               09.D.a; 09.D.b; 09.D.c; 09.D.d; 09.D.e; 09.D.f; 09.D.g; 09.D.h; 09.D.i;       09.D.j; 09.D.k;                                                               09.D.l; 09.E.a; 09.E.b; 09.E.c; 09.E.d; 09.E.e; 09.E.f; 09.E.g; 09.E.h;       09.E.i; 09.E.j;                                                               09.E.k; 09.E.l; 09.F.a; 09.F.b; 09.F.c; 09.F.d; 09.F.e; 09.F.f; 09.F.g;       09.F.h; 09.F.i;                                                               09.F.j; 09.F.k; 09.F.l; 09.G.a; 09.G.b; 09.G.c; 09.G.d; 09.G.e; 09.G.f;       09.G.g; 09.G.h;                                                               09.G.i; 09.G.j; 09.G.k; 09.G.l; 09.H.a; 09.H.b; 09.H.c; 09.H.d; 09.H.e;       09.H.f; 09.H.g;                                                               09.H.h; 09.H.i; 09.H.j; 09.H.k; 09.H.l; 09.I.a; 09.I.b; 09.I.c; 09.I.d;       09.I.e; 09.I.f; 09.I.g;                                                       09.I.h; 09.I.i; 09.I.j; 09.I.k; 09.I.l; 10.A.a; 10.A.b; 10.A.c; 10.A.d;       10.A.e; 10.A.f;                                                               10.B.a; 10.B.b; 10.B.c; 10.B.d; 10.B.e; 10.B.f; 10.C.a; 10.C.b; 10.C.c;       10.C.d; 10.C.e;                                                               10.C.f; 10.D.a; 10.D.b; 10.D.c; 10.D.d; 10.D.e; 10.D.f; 11.A.a; 11.A.b;       11.A.c; 11.A.d;                                                               11.A.e; 11.A.f; 11.B.a; 11.B.b; 11.B.c; 11.B.d; 11.B.e; 11.B.f; 11.C.a;       11.C.b; 11.C.c;                                                               11.C.d; 11.C.e; 11.C.f; 11.D.a; 11.D.b; 11.D.c; 11.D.d; 11.D.e; 11.D.f;       12.A.a; 12.A.b;                                                               12.A.c; 12.A.d; 12.A.e; 12.A.f; 12.A.g; 12.A.h; 12.A.i; 12.A.j; 12.A.k;       12.A.l; 12.B.a;                                                               12.B.b; 12.B.c; 12.B.d; 12.B.e; 12.B.f; 12.B.g; 12.B.h; 12.B.i; 12.B.j;       12.B.k; 12.B.l;                                                               12.C.a; 12.C.b; 12.C.c; 12.C.d; 12.C.e; 12.C.f; 12.C.g; 12.C.h; 12.C.i;       12.C.j; 12.C.k;                                                               12.C.l; 12.D.a; 12.D.b; 12.D.c; 12.D.d; 12.D.e; 12.D.f; 12.D.g; 12.D.h;       12.D.i; 12.D.j;                                                               12.D.k; 12.D.l; 12.E.a; 12.E.b; 12.E.c; 12.E.d; 12.E.e; 12.E.f; 12.E.g;       12.E.h; 12.E.i;                                                               12.E.j; 12.E.k; 12.E.l; 12.F.a; 12.F.b; 12.F.c; 12.F.d; 12.F.e; 12.F.f;       12.F.g; 12.F.h;                                                               12.F.i; 12.F.j; 12.F.k; 12.F.l; 12.G.a; 12.G.b; 12.G.c; 12.G.d; 12.G.e;       12.G.f; 12.G.g;                                                               12.G.h; 12.G.i; 12.G.j; 12.G.k; 12.G.l; 12.H.a; 12.H.b; 12.H.c; 12.H.d;       12.H.e; 12.H.f;                                                               12.H.g; 12.H.h; 12.H.i; 12.H.j; 12.H.k; 12.H.l; 12.I.a; 12.I.b; 12.I.c;       12.I.d; 12.I.e;                                                               12.I.f; 12.I.g; 12.I.h; 12.I.i; 12.I.j; 12.I.k; 12.I.l; 13.A.a; 13.A.b;       13.A.c; 13.A.d; 13.A.e;                                                       13.A.f; 13.B.a; 13.B.b; 13.B.c; 13.B.d; 13.B.e; 13.B.f; 13.C.a; 13.C.b;       13.C.c; 13.C.d;                                                               13.C.e; 13.C.f; 13.D.a; 13.D.b; 13.D.c; 13.D.d; 13.D.e; 13.D.f; 14.A.a;       14.A.b; 14.A.c;                                                               14.A.d; 14.A.e; 14.A.f; 14.A.g; 14.A.h; 14.A.i; 14.A.j; 14.A.k; 14.A.l;       14.B.a; 14.B.b;                                                               14.B.c; 14.B.d; 14.B.e; 14.B.f; 14.B.g; 14.B.h; 14.B.i; 14.B.j; 14.B.k;       14.B.l; 14.C.a;                                                               14.C.b; 14.C.c; 14.C.d; 14.C.e; 14.C.f; 14.C.g; 14.C.h; 14.C.i; 14.C.j;       14.C.k; 14.C.l;                                                               14.D.a; 14.D.b; 14.D.c; 14.D.d; 14.D.e; 14.D.f; 14.D.g; 14.D.h; 14.D.i;       14.D.j; 14.D.k;                                                               14.D.l; 14.E.a; 14.E.b; 14.E.c; 14.E.d; 14.E.e; 14.E.f; 14.E.g; 14.E.h;       14.E.i; 14.E.j;                                                               14.E.k; 14.E.l; 14.F.a; 14.F.b; 14.F.c; 14.F.d; 14.F.e; 14.F.f; 14.F.g;       14.F.h; 14.F.i;                                                               14.F.j; 14.F.k; 14.F.l; 14.G.a; 14.G.b; 14.G.c; 14.G.d; 14.G.e; 14.G.f;       14.G.g; 14.G.h;                                                               14.G.i; 14.G.j; 14.G.k; 14.G.l; 14.H.a; 14.H.b; 14.H.c; 14.H.d; 14.H.e;       14.H.f; 14.H.g;                                                               14.H.h; 14.H.i; 14.H.j; 14.H.k; 14.H.l; 14.I.a; 14.I.b; 14.I.c; 14.I.d;       14.I.e; 14.I.f; 14.1.g;                                                       14.I.h; 14.I.i; 14.I.j; 14.I.k; 14.I.l; 15.A.a; 15.A.b; 15.A.c; 15.A.d;       15.A.e; 15.A.f;                                                               15.B.a; 15.B.b; 15.B.c; 15.B.d; 15.B.e; 15.B.f; 15.C.a; 15.C.b; 15.C.c;       15.C.d; 15.C.e;                                                               15.C.f; 15.D.a; 15.D.b; 15.D.c; 15.D.d; 15.D.e; 15.D.f; 16.A.a; 16.A.b;       16.A.c; 16.A.d;                                                               16.A.e; 16.A.f; 16.B.a; 16.B.b; 16.B.c; 16.B.d; 16.B.e; 16.B.f; 16.C.a;       16.C.b; 16.C.c;                                                               16.C.d; 16.C.e; 16.C.f; 16.D.a; 16.D.b; 16.D.c; 16.D.d; 16.D.e; 16.D.f;       17.A.a; 17.A.b;                                                               17.A.c; 17.A.d; 17.A.e; 17.A.f; 17.B.a; 17.B.b; 17.B.c; 17.B.d; 17.B.e;       17.B.f; 17.C.a;                                                               17.C.b; 17.C.c; 17.C.d; 17.C.e; 17.C.f; 17.D.a; 17.D.b; 17.D.c; 17.D.d;       17.D.e; 17.D.f.                                                               __________________________________________________________________________

Utilities

The compounds of this invention are useful per se or as intermediates inthe preparation of polymers having a wide variety of diagnostic,therapeutic and industrial utilities.

The compounds are useful in the preparation of polyphosphonate flameretardants. The compounds of this invention that contain nonresonantsites of unsaturation, e.g., enolpyran and R³ or Z groups, areincorporated into polyvinyl polymers by methods or analogous methodsheretofore employed with known vinylphosphonates. The compounds of thisinvention that do not already contain vinyl groups or the like areuseful nonetheless as intermediates preparing vinylphosphonate monomers.These monomers are copolymerized with vinyl resins by free radicalcatalysis methods already known per se, e.g., by use of persulfate orelectron beam. Other methods of incorporation of the compounds of thisinvention into polymeric resins will be readily apparent to the skilledartisan, so it is not necessary to use vinyl intermediates.

The compounds of this invention are useful as intermediates in preparinglabelled oligonucleotide probes or, when Y is an oligonucleotide, aredirectly useful in assays for target nucleic acid sequences. Typically,the phosphonate group of the compounds of this invention is covalentlybonded to the terminus of an oligonucleotide having a predeterminedsequence, although any hydroxyl group is useful for this purpose. Thestructure or sequence of the oligonucleotide is not important exceptinsofar as it is binding-competent for its complementary sequence. Manyoligonucleotides having this property are well known, e.g. conventionalphosphodiester or phosphorothioate oligonucleotides.

The compounds of this invention generally will be terminallyincorporated into the oligonucleotide. If they contain a free hydroxylgroup (ordinarily one or both of the R¹ groups or Z) linked to the pyranor (preferably) the furan ring, they optionally are incorporatedinternally into the sequence of the oligonucleotide. Terminallyincorporated diphosphoryl compounds of this invention which contain nofree hydroxyl capable of participating in chain elongation also areuseful in DNA sequencing in essentially the same manner as deoxyNTPshave been used in the past (see example 8 of U.S. Pat. No. 5,276,143).The nucleotide analogues of the invention (when diphosphorylated) areuseful as chain terminators for dideoxynucleotide-type DNA sequencingprotocols, provided that the nucleotide analogue lacks a free hydroxylgroup suitable for polymerase mediated chain elongation. These compoundswill not have a free hydroxyl group at R^(1a) , R^(1b) or Z and do notpossess a cyclic structure incorporting the phosphorus atom (althoughsuch excluded structures can be intermediates). The nucleotide analogueis included in a kit with other reagents (such as klenow polymerase orT4 polymerase, dNTPs, etc) needed for DNA sequencing (Otvos, et al,"Nucl. Acids Res." 15:1763-1777 (1987).

If the oligonucleotide-incorporated compound of this invention isbinding-competent for its complementary sequence, i.e., if it is capableof base-pairing, then this nucleotide monomer will participate inhybridization. It is not necessary, however, that the incorporatednucleotide analogue of this invention base pair or otherwise participatein hybridization. If it is located at the terminus of theoligonucleotide it will be useful as an immunological recognition siteto detect the presence of the oligonucleotide when used as a probe or asa linker for a detectable group.

The compounds of this invention are useful as linkers or spacers inpreparing affinity absorption matrices, immobilized enzymes for processcontrol, or immunoassay reagents. The compounds herein contain amultiplicity of functional groups that are suitable as sites forcross-linking desired substances. For example, it is conventional tolink affinity reagents such as hormones, peptides, antibodies, drugs,and the like to insoluble substrates. These insolublized reagents areemployed in known fashion to absorb binding partners for the affinityreagents from manufactured preparations, diagnostic samples and otherimpure mixtures. Similarly, immobilized enzymes are used to performcatalytic conversions with facile recovery of enzyme. Bifunctionalcompounds are commonly used to link analytes to detectable groups inpreparing diagnostic reagents.

Many functional groups in the compounds of this invention are suitablefor use in cross-linking. For example, the phosphonic acid is used toform esters with alcohols or amides with amines. The Z, R^(1a) or R^(1b)groups substituted with OH, azido (which is reduced to amino if desiredbefore cross-linking), CN or halo are suitable sites. Similarly, theamino, halo, acyl and other reactive sites (e.g., the 8-purine position)found on group B are suitable. Suitable protection of reactive groupswill be used where necessary while assembling the cross-linked reagent.In general, the compounds here are used by linking them throughphosphonic acid to the hydroxyl or amino groups of the linking partnerin the same fashion as shown herein and covalently bonded to the otherbinding partner through a Z, B, R^(1a) or R^(1b) group. For example afirst binding partner such as a steroid hormone is esterified to thephosphonic acid of this invention and then this conjugate iscross-linked to cyanogen bromide activated Sepaharose, wherebyimmobilized steroid is obtained. Other chemistries for conjugation arewell known. See for example Maggio, "Enzyme-Immunoassay" (CRC, 1988, pp71-135) and references cited therein.

The oligonucleotides of this invention are labelled with anyconventional detectable label, e.g. a fluorescent moiety such asfluorescein, radioisotopes such as C₁₄ or H₃, stable free radicals,avidin, biotin and the like all of which previously have been used aslabels for immunoassays or diagnostic probes. The label will be presenton the oligonucleotide or on the residue of the nucleotide analogue ofthis invention. Suitable labelling methods are well known and arereadily used with reactive groups such as hydroxyl, allyl and the like.A simple method is to label the compound of this invention with H₃ byproton exchange. The compounds also are biotinylated using conventionalmethods. See for instance U.S. Pat. No. 5,276,143 for analogousstructures. However, the oligonucleotides of this invention also areuseful directly in diagnostic probe assays without an exogenousdetectable label. In one embodiment of this alternative, antibodies areraised against the nucleotide analogues of this invention. Suchantibodies (which in turn are labelled or used in a double antibodyconfiguration) bind to the analogue of this invention and thereby areuseful in detecting the presence of the bound probe that incorporatesthe nucleotide analogue of this invention.

The compounds of the invention, particularly those in which thephosphonate and base have the same absolute stereochemistry, are usefulfor treatment of microbial infections, for treatment of tumors or forother indications described below. Microbial infections treatable by thecompounds of this invention include viruses, parasites, yeasts andfungi, but it is believed that the compounds are most effective againstviruses, which constitutes the preferred utility. Exemplary viralinfections include infections caused by DNA or RNA viruses includingherpesviruses (CMV, HSV 1, HSV 2, EBV, varicella zoster virus, bovidherpesvirus type 1, equid herpesvirus type 1), papillomaviruses (HPVtypes 1-55; carcinogenic HPV), flaviviruses (including African swinefever virus and Japanese encephalitis virus), togaviruses (includingVenezuelan equine encephalomyelitis virus), influenza viruses (typesA-C), retroviruses (HIV 1, HIV 2, HTLV I, HTLV II, SIV, HBV, FeLV, FIV,MoMSV), adenoviruses (types 1-8), poxviruses (vaccinia virus),enteroviruses (polio virus type 1-3, hepatitis A virus), gastroenteritisviruses (Norwalk viruses, rotaviruses), hantaviruses (Hantaan virus),papovaviruses, rhinoviruses, parainfluinza virus types 1-4, rabiesvirus, RSV, hepatitis viruses A, B, C and E, and the like. The structure(1) compounds in which Z is CH₂ OR² are believed to be most effectiveagainst DNA viruses, while those in which Z is CH₃, CH═CH₂, CH₂ N₃,C.tbd.CH, or haloalkyl are believed to be most effective against RNA andretroviruses. Compounds in which Z is H are believed to be effective toat least some degree against DNA, RNA and retroviruses. Hepatitis Bviruses and HIV are believed to be most effectively treated by the β-Lcompounds of this invention.

The antiviral activity of individual nucleotide analogues is determinedby routine assay of antiviral (or other antimicrobial) activity usingenzyme inhibition assays, tissue culture assays, animal model assays andthe like as will be understood by those skilled in the art.

Protozoan parasite infections are treated using the compounds of theinvention. The term protozoa includes those members of the subphylaSarcomastigophora and Sporozoa of the phylum Protozoa. Moreparticularly, the term protozoa as used herein includes genera ofparasitic protozoa which are important to man because they either causedisease in man or in his domestic animals. These genera for the mostpart are classified in the superclass Mastighphora of the subphylumSarcomastigophora and the class Telosporea of the subphylum Sporozoa inthe classification according to Baker (1969). Illustrative genera ofthese parasitic protozoa include Histomonas, Pneumocystis, Trypanosoma,Giardia, Trichomonas, Eimeria, Isopora, Leishmania, Entamoeba,Toxoplasma and Plasmodium. Parasitic protozoans include Plasmodiumfalciparum, Plasmodium berghei, Plasmodium malariae, Plasmodium vivax,Leishmania braziliensis, Leishmania donovani, Trypanosoma cruzi,Trypanosoma brucei, Trypanosoma rhodesiense, Pneumocystis carinii,Entamoeba histolytica, Trichomonas vaginalis and the like (de Vries, E.,et al, "Mol. Biochem. Parasitol" 47:43-50 (1991)). The compounds inwhich Z is CH₂ OR² and B is 3-deazaadenine are particularly interestingfor malarial parasites.

Nucleoside analogues of the invention are used to treat yeast or fungalinfections caused by Candida glabrata, Candida tropicalis, Candidaalbicans, and other Candida species Cryptococcus species includingCryptococcus neoformans, Blastomyces species including Blastonycesdermatidis, Torulopsis species including Torulopsis glabrata,Coccidioides species including Coccidioides immitis, Aspergillus speciesand the like.

The therapeutically useful compounds of this invention in which hydroxylor amino groups are protected are useful as oral or sustained releaseforms. In these uses the protecting group is removed in vivo, e.g.,hydrolyzed or oxidized, so as to yield the free amino or hydroxyl. Thisis necessary in the case of the phosphonate hydroxyl groups. Suitableesters or amidates for this utility are selected based on the substratespecificity of esterases and/or carboxypeptidases expected to be foundwithin cells where precursor hydrolysis is desired. To the extent thatthe specificity of these enzymes is unknown, one will screen a pluralityof nucleotide analogues of this invention until the desired substratespecificity is found. This will be apparent from the appearance of freephosphonate or of antimicrobial activity. One generally selectscompounds that are (i) not hydrolyzed or hydrolyzed comparatively slowlyin the upper gut, (ii) gut and cell permeable and (iii) hydrolyzed inthe cell cytoplasm and/or systemic circulation. Screens with cells fromparticular tissues are used to identify precursors that are released inorgans susceptible to a target viral or microbial infection, e.g. in thecase of liver, precursor drugs capable of hydrolysis in the liver. Otherinfections, e.g. CMV or HIV, optionally are treated with a precursorthat is hydrolyzed at substantially the same rate and to substantiallythe same degree in all tissues. Assays known in the art are suitable forthese purposes, including intestinal lumen stability, cell permeation,liver homogenate stability and plasma stability assays. These assays areused to determine the bioavailability characteristics of the precursors.However, even if the derivatives are not converted in vivo they remainuseful as chemical intermediates.

The nucleotide analogues of the invention also can be (1) applied totissue culture systems to eliminate or reduce viral spread or growthduring the production of biopharmaceuticals or other products (such asproteins or vaccines), (2) used to eliminate or reduce viral spread orgrowth in clinical samples (such as blood), and (3) used to stop growthof tissue culture or bacterial cells (using toxic amounts of compound)while leaving the cells to carry on with protein production.

Pharmaceutical formulations. Compounds of the invention and theirphysiologically acceptable salts (hereafter collectively referred to asthe active ingredients) are formulated for administration by any routeappropriate to the condition to be treated. The compounds andformulations preferably will be sterile.

The active ingredients are placed into pharmaceutical formulations. Theformulations, both for veterinary and for human use, comprise at leastone active ingredient, as above defined, together with one or moreacceptable carriers therefor and optionally other therapeuticingredients. The carrier(s) must be "acceptable" in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient.

The formulations conveniently are presented in unit dosage form and maybe prepared by any of the methods well known in the art of pharmacy. Ingeneral the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both, and then, if necessary, shapingthe product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as solution or a suspension in an aqueous liquid ora non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

For external infections of the eye or other external tissues e.g. mouthand skin, the formulations are preferably applied as a topical ointmentor cream containing the active ingredient(s) in an amount of, forexample, 0.075 to 20% w/w (including active ingredient(s) in a rangebetween 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7%w/w, etc), typically 0.2 to 15% w/w and most typically 0.5 to 10% w/w.When formulated in an ointment, the active ingredients may be employedwith either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulphoxide andrelated analogues.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. This phase may comprise anemulsifier alone, or a mixture of at least one emulsifier with a fat oran oil or with both a fat and an oil. Preferably, a hydrophilicemulsifier is included together with a lipophilic emulsifier which actsas a stabilizer. It is also preferred to include both an oil and a fat.Emulsion stabilizers suitable for use in the formulation of the presentinvention include Tween® 60, Span® 80, cetostearyl alcohol, benzylalcohol, myristyl alcohol, glyceryl mono-stearate and sodium laurylsulfate. Suitable oils or fats include straight or branched chain, mono-or dibasic alkyl esters such as di-isoadipate, isocetyl stearate,propylene glycol diester of coconut fatty acids, isopropyl myristate,decyl oleate, isopropyl palmitate, butyl stearate or 2-ethylhexylpalmitate. These may be used alone or in combination depending on theproperties required. Alternatively, high melting point lipids such aswhite soft paraffin and/or liquid paraffin or other mineral oils can beused.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is typically is present in suchformulations in a concentration of 0.01 to 20% by weight.

Formulations suitable for nasal administration wherein the carrier is asolid include a coarse powder having a particle size for example in therange 20 to 500 microns (including particle sizes in a range between 20and 500 microns in increments of 5 microns such as 30 microns, 35microns, etc), which is administered by rapid inhalation through thenasal passage from a container of the powder. Suitable formulationswherein the carrier is a liquid, for administration as for example anasal spray or as nasal drops, include aqueous or oily solutions of theactive ingredient. Formulations suitable for aerosol administration maybe prepared according to conventional methods and may be delivered withother therapeutic agents such as pentamidine for treatment ofpneumocystis pneumonia.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described. Preferred unit dosage formulations arethose containing a daily dose or unit daily sub-dose, as herein aboverecited, or an appropriate fraction thereof, of an active ingredient.

The present invention further provides veterinary compositionscomprising at least one active ingredient as above defined together witha veterinary carrier therefor. Veterinary carriers are materials foradministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds of the invention can be used to provide controlled releasepharmaceutical formulations containing as active ingredient one or morecompounds of the invention in which the release of the active ingredientis controlled and regulated to allow less frequent dosing or to improvethe pharmacokinetic or toxicity profile of a given compound. In general,the compounds are administered from controlled release systems such asthe intravitreal implant of WO 92/14450 or U.S. Pat. No. 5,098,443, orthe matrices of U.S. Pat. No. 4,740,365 or U.S. Pat. No. 5,141,752,although many others are known and are suitable for use herein.

Therapeutic Administration. Suitable routes for administration includeoral, rectal, nasal, topical (including ocular, buccal and sublingual),vaginal and parenteral (including subcutaneous, intramuscular,intravitreal, intravenous, intradermal, intrathecal and epidural). Thepreferred route of administration will depend upon the condition of thepatient, the toxicity of the compound and the site of infection, amongother considerations known to the clinician.

For each of the above-indicated theapeutic indications the amountrequired of an active ingredient (as above defined) will depend upon anumber of factors including the severity of the condition to be treated,the infectious agent, whether the use is prophylactic or to treat anacute infection, the site of infection or pathology (e.g. CMV retinitisis treated systemically or by intravitreal injection) and other factorsultimately at the discretion of the attending physician or veterinarian.In general, however, a suitable dose for consideration by the clinicianwill be in the range of analogous methoxyphosphonates (see supra),taking into account differences in potency, generally 0.1 to 250 mg perkilogram bodyweight of recipient per dose (including activeingredient(s) in a range between 0.1 mg and 250 mg/Kg/dose in incrementsof 0.5 mg/Kg/dose such as 2.5 mg/Kg/dose, 3.0 mg/Kg/dose, 3.5mg/Kg/dose, etc), typically in the range 0.5 to 50 mg per kilogram bodyweight per dose and most usually in the range 1 to 15 mg per kilogrambody weight per dose. Unless otherwise indicated all weights of activeingredient are calculated as a compound of structure (1) wherein Y isnot a polymer.

The desired dose is administered at appropriate intervals in unit dosageforms, usually with a relatively higher induction dose and lower, lessfrequent maintenance doses. The compounds also are usedprophylactically, for example, by administration on about from 1 to 7days before viral infection. HPV tumors or growths and herpes lesionsoften are treated topically, either by local injection or by topicalgels, ointments or the like.

Compounds such as those of structures (2), (3), and (4) generally areexpected to have a higher oral bioavailability than the correspondinguncyclized nucleotide analogue and/or exhibit reduced toxicity whencompared with the same dose of the corresponding uncyclized nucleotideanalogue. Doses will be adjusted accordingly.

The compounds of the invention optionally are employed in combinationwith other therapeutic agents for the treatment or prophylaxis of theinfections or conditions indicated above. Examples of such furthertherapeutic agents include agents that are effective for the treatmentor prophylaxis of viral, parasitic or bacterial infections or associatedconditions or for treatment of tumors or related conditions. Theseinclude 3'-azido-3'-deoxythymidine (zidovudine, AZT),2'-deoxy-3'-thiacytidine (3TC), 2',3'-dideoxy-2',3'-didehydroadenosine(D4A), 2',3'-dideoxy-2',3'-didehydrothymidine (D4T), carbovir(carbocyclic 2',3'-dideoxy-2',3'-didehydroguanosine),3'-azido-2',3'-dideoxyuridine, 5-fluorothymidine,(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), 2-chlorodeoxyadenosine,2-deoxycoformycin, 5-fluorouracil, 5-fluorouridine,5-fluoro-2'-deoxyuridine, 5-trifluoromethyl-2'-deoxyuridine,6-azauridine, 5-fluoroorotic acid, methotrexate, triacetyluridine,1-(2'-deoxy-2'-fluoro-1-β-arabinosyl)-5-iodocytidine (FIAC),tetrahydro-imidazo(4,5,1-jk)-(1,4)-benzodiazepin-2(1H)-thione (TIBO),2'-nor-cyclicGMP, 6-methoxypurine arabinoside (ara-M), 6-methoxypurinearabinoside 2'-O-valerate, cytosine arabinoside (ara-C),2',3'-dideoxynucleosides such as 2',3'-dideoxycytidine (ddC),2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI), acyclicnucleosides such as acyclovir, penciclovir, famciclovir, ganciclovir,HPMPC, PMEA, PMEG, PMPA, PMPDAP, FPMPA, HPMPA and HPMPDAP, (2R, 5R)-9-tetrahydro-5-(phosphonomethoxy)-2-furanyl!adenine, (2R, 5R)-1-tetrahydro-5-(phosphonomethoxy)-2-furanyl!thymine, other antiviralsincluding ribavirin (adenine arabinoside), 2-thio-6-azauridine,tubercidin, aurintricarboxylic acid, 3-deazaneoplanocin, neoplanocin,rimantidine, adamantine, and foscarnet (trisodium phosphonoformate),antibacterial agents including bactericidal fluoroquinolones(ciprofloxacin, pefloxacin and the like), aminoglycoside bactericidalantibiotics (streptomycin, gentamicin, amicacin and the like),β-lactamase inhibitors (cephalosporins, penicillins and the like), otherantibacterials including tetracycline, isoniazid, rifampin,cefoperazone, claithromycin and azithromycin, antiparasite or antifungalagents including pentamidine (1,5-bis(4'-aminophenoxy)pentane),9-deazainosine, sulfamethoxazole, sulfadiazine, quinapyramine, quinine,fluconazole, ketoconazole, itraconazole, Amphotericin B,5-fluorocytosine, clotrimazole, hexadecylphosphocholine and nystatin,renal excretion inhibitors such as probenicid, nucleoside transportinhibitors such as dipyridamole, dilazep and nitrobenzylthioinosine,immunomodulators such as FK506, cyclosporin A, thymosin α-1, cytokinesincluding TNF and TGF-β, interferons including IFN-α, IFN-β and IFN-γ,interleukins including interleukin 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 13,macrophage/granulocyte colony stimulating factors including GM-CSF,G-CSF, M-CSF, cytokine antagonists including anti-TNF antibodies,anti-interleukin antibodies, soluble interleukin receptors, proteinkinase C inhibitors and, particularly in treatment of HIV, cotherapywith IFN-α, IL-2 or IL-12.

Immunogens and Antibodies. The compounds of this invention are used asimmunogens to prepare antibodies capable of binding specifically to thecompounds or their metabolic products. The immunogenic compositions areuseful as intermediates in the preparation of antibodies for use indiagnostic or quality control assays for the compounds or theirmetabolic products. The antibodies are useful for measuring thepresence, absence or amounts of the compounds by any convenienthomogenous or heterogenous procedure such as fluorescence polarizationimmunoassay, fluorescence immunoassay (using fluorescent labels such asfluorescein and the like), radioimmunoassay, enzyme immunoassay (usingenzyme indicators such as alkaline phosphatase, horseradish peroxidase,glucose oxidase, urease and the like) and nephelometric inhibition assayby described methods (WO 92/22639). Competitive-type assays usuallyrequire the antibody, and a tracer (such as a fluorescent or radiolabel) conjugated to the compound to be assayed. The antibodies directedagainst the compounds of this invention desirably will not cross-reactwith naturally-occurring nucleotides or nucleosides.

The immunogens of this invention contain the precursor or hydrolyticproducts in association with an immunogenic substance such as a proteinor peptide. Immunogenic substances include adjuvants such as Freund'sadjuvant, immunogenic proteins such as viral, bacterial, yeast, plantand animal polypeptides, in particular keyhole limpet hemocyanin, serumalbumin, bovine thyroglobulin or soybean trypsin inhibitor, andimmunogenic polysaccharides.

Methods for the manufacture hapten immunogens are conventional per se,and are useful here, taking into account the functional groups that areavailable for cross-linking. The polypeptide immunogen (or a polypeptidethat is desired to be made immunogenic by cross-linking to a compound ofthis invention) may be conjugated to a site on the heterocyclic baserather than to the phosphonate moiety. In general, the site will be anamino group located on the purine or pyrimidine moiety of the nucleotidephosphonate, at the 5 position of pyrimidines (such as cytosine oruracil), at the 1 position of purines (such as adenosine or guanine) orthrough a furan or pyran ring hydroxyl group (usually at the R^(1a),R^(1b) or Z positions). Alternatively, the precursor compound iscross-linked through the phosphonate, typically by amidation oresterification of the phosphonate by the polypeptide itself or by across-linking functionality covalently bonded to the polypeptide,whereby Y is an immunogenic protein having more than 50 amino acidresidues, usually less than 1000. The conjugates are prepared inconventional fashion. For example, N-hydroxysuccinimide, succinicanhydride or alkN═C═Nalk are useful in preparing the conjugates of thisinvention. Animals typically are immunized against the immunogenicconjugates and monoclonal antibodies prepared in conventional fashion.

Synthetic Methods

The Table 1 saturated compounds are made by the following scheme 1.Table 1 unsaturated compounds are made by scheme 2 or straight-forwardvariations thereof. Scheme 2 also is readily adapted to make saturatedTable 1 compounds by adding the R¹ groups across the double bond, forexample, via expoxidation, hydroxylation, reduction or halogenation.Table 1 compounds having R^(1a) and R^(1b) joined with the heterocyclicring to form cyclopropyl are produced by carbene addition across thedouble bond of the corresponding unsaturated ring. Table 1 compound 14is made by the method of scheme 3a. Compounds of this invention in whichY is CH₃, H, CH═CH₂, alkylhalo, CH₂ N₃ or C.tbd.CH are made by theprocedures of scheme 3 or variations thereof that will be apparent tothe ordinary artisan in this field. These schemes are used with any baseB, provided that the base is suitably protected during synthesis. Othercompounds of this invention are made by variations of these schemes thatwill be readily apparent to those skilled in the art.

These schemes employ conventional abbreviations for known reagents.##STR38##

The step in scheme 2 where (21) is converted to (22) by double bondmigration is inventive. A protected, Z-substituted pyran (I) is treatedin accord with this step, and any Lewis Acid (e.g. HCl, ZnCl₂, BF₃.OEt₂,SnCl₃, and the like) is suitable. The reaction solvent is not critical;any high boiling (>100° C.) organic solvent is satisfactory. Thephosphite PRT group is not critical and usually falls within R³,typically lower alkyl (C₁ -C₆) and preferably iPr or ethyl.

Also inventive is the step in scheme 2 where the double bond in (26)migrates to the 1-2 position as shown for compound (27). A protected,Z-substituted pyran (III) is treated with any base, whether organic orinorganic, whereupon the double bond spontaneously migrates to aposition α to the phosphate atom. The β anomers require a stronger basethan do the α anomers. This method has the additional advantage ofremoving benzyl protecting groups from any exocyclic amino groups of B.PRT in this method generally is selected from R³ as noted in theprevious paragraph.

The various diastereomers falling within the scope of this invention arereadily produced from the corresponding sugars using the foregoingschemes. For example, ##STR39## is produced from D-rhamnal, ##STR40## isproduced from D-glactal, ##STR41## is produced by 6-deoxy-D-glactal; and##STR42## is produced from D-xylal. In general, other suitable sugars orunsaturated analogues thereof will be readily apparent startingmaterials. L-isomers of the claimed compounds are derived from thecorresponding L-sugars or analogues thereof, taking into account thestereochemical shift upon substitution by heterocylic base (see scheme2). Aside from the foregoing, the following Table 6 lists each of thesugars from which the Table 1 structures are derived.

                  TABLE 6                                                         ______________________________________                                        1.   D-allose      18.   D-gulose 35. D-ribose                                2.   D-glucose     19.   L-galactose                                                                            36. L-lyxose                                3.   D-altrose     20.   D-allose 37. D-xylose                                4.   D-mannose     21.   D-galactose                                                                            38. L-xylose                                5.   D-glucal      22.   L-glucose                                                                              39. D-lyxose                                6.   L-galactal    23.   L-allose 40. D-arabinose                             7.   D-glucal      24.   L-gulose 41. D-xylose                                8.   L-galactal    25.   D-glucose                                                                              42. D-lyxose                                9.   D-glucal      26.   L-mannose                                                                              43. D-arabinose                             10.  D-galactal    27.   L-gulose 44. D-ribose                                11.  L-glucal      28.   D-allose 45. L-arabinose                             12.  L-galactal    29.   D-glucose                                                                              46. L-ribose                                13.  D-glucal      30.   D-altrose                                                                              47. L-xylose                                14.  2-deoxy-D-glucose                                                                           31.   L-idose  48. L-arabinose                             15.  D-galactal    32.   L-gulose 49. L-ribose                                16.  L-galactal    33.   L-talose 50. L-xylose                                17.  L-glucal      34.   L-galactose                                          ______________________________________                                    

If racemization occurs during any step in the synthesis the variousdiastereomers at chiral atoms 1-6 are separated using standard methodssuch as HPLC, RPLC or crystallization.

It is also within the scope of this invention to use compounds fallingwithin the claims as intermediates for other claimed compounds, forexample as shown in scheme 3a or as will be readily apparent to thoseskilled in the art, e.g. interconversion of heterocyclic bases.

Bis amidate synthesis. Synthesis of bis-phosphoroamidate nucleotideanalogues of structure (1) where Y groups are the same and are an aminoacid, dipeptide, tripeptide or polypeptide is accomplished by conversionof the phosphonic acid nucleotide analogue to the correspondingbis-phosphoroamidate compound. The diacid is suspended in approximately2 equivalents of the Y reactant in a solvent such as dry pyridine or DMF(dimethylformamide) optionally containing a non-nucleophilic organicbase such as triethylamine (about 3 to 10 equivalents). The dehydrationstep is accomplished by modification of a described reaction (Mukaiyama,T. et al, "J. Am. Chem. Soc." 94:8528-8532 (1972)) by adding a 1:1mixture of triphenylphosphine (reg. no. 603-35-0; Aldrich) and2,2'-dipyridyl disulfide (2 to 4 equivalents; reg. no. 2127-03-9;Aldrich) in pyridine to the nucleotide analogue/amino acid mixture and(a) stirring at room temperature for about 4 to 16 hours or (b) heatingto 60° C. to 100° C. (including any temperature in one degree Cincrements between 60° and 100° C. such as 70°, 80° or 90° C.) for about4 to 16 hours. The resulting reaction mixture is then concentrated andthe final bis-amidate product is recovered and purified by conventionalmethods.

An alternative reaction suitable for synthesizing most amidate compoundsis to convert the phosphonate to the corresponding chloridate byreaction with thionyl chloride in solvent (DMF) as described in EP 481214. An amino acid, dipeptide or other molecule bearing a free amine isthen reacted with the chloridate to yield the corresponding mono-amidate(where the phosphonate is cyclized) or bis-amidate.

Synthesis of compounds of structure (1) having amino acids that containamino, guanidino or carboxyl groups (such as lys, arg, his, asn, gln,lys-lys, arg-arg, lys-arg and the like) is accomplished by the samemethod, but using protected amine or carboxyl groups. After synthesis ofthe protected amidate compound, the protecting groups are removed byconventional methods. Suitable protecting groups are well known (seesupra) and include acid labile groups such as p-tosyl, BOC(t-butoxycarbonyl) and FMOC (fluorene methoxycarbonyl) for protectingamine groups. Groups such as t-butyl, methyl, ethyl, benzyl and the likecan be used to protect carboxyl groups. These groups are removed underacid, base or hydrogenolysis conditions or are removed with an esteraseaccording to conventional methods.

Synthesis of compounds of structure (1) having amino acids such as tyr,cys, ser and thr is accomplished by optionally protecting hydroxyl orthiol groups using protecting groups know in the art. For example, thehydroxyl group of ser, thr or tyr can be protected using benzyl, ethyland the like and the thiol group of cys can be protected using trityl,p-methylbenzyl and the like. The choice of a protecting group willdepend on the stability of the bis-amidate toward conditions used toremove a particular protecting group. Appropriate protecting groups canbe selected or determined by the skilled artisan using routine methods.

Synthesis of compounds in which Y is N-alkylamine is accomplishedessentially as described by Saito, "Chem. Pharm. Bull." 39:3207 (1991).

Amidate-ester synthesis. Synthesis of mixed amidate-ester nucleotideanalogues where one Y is an amino acid ester and the other is a group ofthe formula OR³ is accomplished by conversion of the nucleotide analoguedi- or bis-ester to the corresponding mono ester by treatment with abase such as ammonia to remove one ester group. The resulting mono esteris then converted to a mixed amidate-ester as described for synthesis ofbis amidate compounds.

Oligonucleotides. Compounds of this invention where Y is anoligonucleotide are prepared from parental monomers in which Y is OH.The monomers are converted to the reactive intermediate usingconventional chemistry, for example the method of Uhlmann et al.,"Chemical Reviews" 90(4):543 at 553, part c and FIG. 23 (1990) or Mazuret al., "Tet. Let." 40(20):3949 at scheme (1) and page 3955 (1984). Forexample, an oligonucleotide chain is synthesized on a matrix such ascontrolled pore glass in the 3'-5' or 5' to 3' direction, whereby the 3'or 5' ends, respectively of the oligonucleotide are bonded to the matrixand the oligonucleotide is protected except for the terminal 5' or 3'hydroxyl, respectively, of the last nucleotide. The protectedo-chlorophenyl derivative of the structure 1 compound is prepared,analogous to the starting material shown in FIG. 23 of Uhlmann et al.This is covalently bonded to a terminal OH of the oligonucleotide usingthe Uhlmann et al. method.

Alternatively, the compound of this invention is converted to theintermediate that is analogous to compound 12 of Mazur et al. Thisanalogue is added to the oligonucleotide using essentially thedinucleotide preparative chemistry shown on page 3955 of Mazur et al.The pyridinium salt of the compound of this invention (without freehydroxyl groups) is condensed with the free 5' or 3' end of theotherwise protected oligonucleotide in the same way Mazur et al.condense phosphonate 12 with a second nucleoside unit using DCC in drypyridine in the presence of Dowex 50. After reaction by either method,the oligonucleotide is separated from the matrix (if present during theaddition of the compound of this invention) and deprotected.

Alternatively, the compounds of this invention are chemically convertedto nucleotide triphosphate analogues. This is accomplished using knownreactions, for example reaction of the phosphonate withtris(tri-n-butylammonium) pyrophosphate in DMF. The resulting deoxyNTPor NTP analogue (where R^(1a) or R^(1b) are unprotected hydroxy) isincorporated enzymatically into the oligonucleotide using ligase orpolymerase.

Esters. Hydroxy esters, especially at the phosphonate, are generallysynthesized as known in the art or as shown below. For instance, see themethods described in EP 481 214 or Mukaiyama, T. et al, "J. Am. Chem.Soc." 94:8528-8532 (1972) . Dialkyl phosphonate esters are synthesizedvia conversion of a dichlorophosphonate chloridate (Quast, H. et al,"Synthesis" 7:489-490 (1974); Quast, H. et al, "Synthesis" 7:490 (1974);Moedritzer, K. et al, "Synth. Reac. Inorg. Met.--Org. Chem." 5:417-27(1974); Stowell, M. H. B., et al, "Tet. Lett." 31:3261-3262 (1990)) to acorresponding dialkylester (or dialkylamide) by reaction with alcohols(or amines). Monoalkylesters (or mono alkylamides) are obtained byhydrolysis of the disubstituted phosphonate in base (NaOH, KOH and thelike). Disubstituted diacyloxyalkyl phosphonates are obtained byreaction of the unsubstituted phosphonate with a substitutedchloromethyl ester (R³ C(O)OCH(R³)Cl). A corresponding monosubstitutedacyloxyalkyl phosphonate is obtained by hydrolysis in acid or base.

Bis esters having R³ groups such as aryl, substituted aryl, alkaryl orsubstituted alkaryl (such as phenyl, alkoxyphenyl, benzyl, alkoxybenzyl)are also synthesized by reaction of the phosphonic acid with thionylchloride and a catalytic amount of DMF in a solvent such asacetonitrile. The resulting dichloridate is then reacted with about 4, 5or 6 equivalents of the sodium or potassium alkoxide or a sodium orpotassium aryloxide obtained from reaction with sodium hydride orpotassium hydride and the alcohol (such as phenol, benzyl alcohol andthe like) in a solvent such as THF or acetonitrile at a reducedtemperature (below about -70° C., preferably about -76° C. to -78° C.).

The internally cyclized analogues having structures (2), (3) and (4) areprepared by a number of suitable methods from the free hydroxyphosphonic acid. These methods include treatment with DCC in DMF,reaction with Vilsmeier's reagent (ClCH═N(CH₃)₂ Cl), or methods ofphosphate activation known per se. In one embodiment of this inventionfor the preparation of the corresponding cyclized compound from theparental phosphonate nucleotide, the phosphonate is (a) treated withClCH═N(CH₃)₂ Cl to yield the phosphonylchloridate and (b) optionally thephosphonylchoridate is reacted with a nucleophile (preferably at lowtemperature, e.g. lower than about -20° C.) such as an alcohol or amineto produce one of the intermediates described above. In a further stepthe product of steps (a) or (b) is subject to hydrolysis or protonolysis(typically acid protonolysis) respectively to yield the cyclic compound.Vilsmeier's reagent is advantageously produced in situ by combiningSOCl₂, PCl₅, POCl₃, COCl₂ or the like with DMF. Advantageously, theproduct of step (a) is not purified or separated from the reactionmixture before being reacted with the nucleophile, a distinct economicadvantage for this synthetic route.

Internally cyclized dihydroxy compounds of this invention where theremaining Y group is an ester or amide typically are made by reactingthe appropriate cyclic compound with SOCl₂ /DMF to yield the activatedphosphonylchloride (see scheme 4), followed by treatment with thecorresponding nucleophile (e.g. alkoxide, phenolate, amine, etc.) toyield the protected intermediate formamidine which is subsequentlyhydrolyzed to the target compound (48). Alternatively, esters can alsobe prepared as depicted in scheme 5. The N-,O- protected intermediatephosphonate diester is obtained. The N- and O- protecting groups aresubsequently removed followed by treatment of the phosphonate diesterwith NaH leading to cyclization yielding target compound. A third methodfor the synthesis of esters of the cyclic compounds entails alkylationof the cyclic compounds using common alkylating agents R³ Lv (where Lvis a leaving group) such as alkyl halides, tosylates, diazoalkanes andthe like (see scheme 6). This method is particularly useful forpreparing acyloxyalkyl esters by treatment of the cyclic compound withthe corresponding acyloxyalkylhalide. In an exemplary method for thepreparation of acyloxyalkyl esters of the cyclic compounds,triethylamine and R³ C(O)OCH₂ Cl are reacted with the cyclic compound.The stoichiometric proportion of triethylamine: R³ C(O)OCH₂ Cl: cycliccompound may be selected to be 1-2:1-2:1. Use of such low proportions ofreactants may lessen side reactions with any exocyclic amino group of Band thereby greatly improve yields.

Each of the following schemes exemplify compound (30) as the nucleotideanalogue. However, any B is employed in place of cytosine, provided thatany exocyclic oxo or amino groups are protected as required. Also, step3 of scheme 4 will be omitted when B contains no exocyclic amine.##STR43##

Methods for linking cholesteryl, saccharide and other moieties toreactive groups have been described (Hadfield, "Adv. Pharmacol.Chemother." 20:21 (1984); Gouyette, "Tet. Lett." 30:6019 (1989);Ksander, "J. Med. Chem." 37:1823 (1994), and are adapted here tosubstitute such Y moieties into the phosphonate).

Bis esters are converted to monoesters by chemical hydrolysis in base oracid according to the bis ester used. For example, treatment with NaOH(0.5 to 2N) or NH₄ OH in a solvent such as THF (tetrahydrofuran),dioxane or an alcohol for 1 to 24 hours at 22° to 90° is suitable formost esters. The choice of solvent will depend on the characteristics ofthe bis ester used. The hydrolytic stability of the phosphonate bisesters is unequal and provides a means for obtaining the monoester.Selection of hydrolysis conditions is determined by routine testing.Alkaline hydrolysis yields the phosphonate monoester and a correspondingalcohol or phenol. Other Y groups are then linked to the monoester usingreagents and conditions (i.e., a 1:1 mixture of triphenylphosphine(PPh₃) and 2,2'-dipyridyl disulfide in a suitable solvent such aspyridine or DMF) essentially as described for synthesis of bis amidates.

Mixed bis amidate synthesis. Synthesis of compounds of structure (1)where both Y are amino acids or where one Y is an amino acid and theother is an amine (NH₂, NHR³, N(R³)₂) is accomplished by directconversion as described above for bis amidates followed by separation ofthe final products. Another method to synthesize mixed bis amidates isamidation of an appropriate phosphonate monoester, followed by removalof the ester group under conditions that do not remove the first amide.Synthesis of phosphonate monoester compounds has been described (EP 481214). Such compounds are then converted to the mixed bis amide bycondensation with a second amino acid or amine as described (i.e., usinga 1:1 mixture of triphenylphosphine and 2,2'-dipyridyl disulfide) toyield the final product.

Mono amidate synthesis. Synthesis of compounds of structure (1) whereone Y is an amino acid and the other is OH is accomplished essentiallyas described for bis amidate synthesis. Cyclic phosphonates are preparedby direct dehydration of the corresponding dihydroxy nucleotide analogueusing DCC (dicyclohexylcarbo-diimide) or4-morpholino-N,N'-dicyclohexylcarboxamide as described (Ho et al. "Mol.Pharmacol." 41:197-202 (1992)). The cyclic phosphonate is condensed withan amino acid ester in the presence of a 1:1 mixture oftriphenylphosphine and 2,2'-dipyridyl disulfide in a suitable solventsuch as pyridine or DMF.

Protected heterocyclic base compounds. The present invention includesnucleotide analogues that comprise a protected heterocyclic base. Thesecompounds are useful as synthetic intermediates and/or, as antiinfectiveor antiviral agents per se.

Exocyclic amines of the compounds of this invention are protected byreacting the nucleotide analogue with R³ C(O)Cl or (CH₃ O)₂ CHR³. Theexocyclic amine groups such as the N⁴ -amine of cytosine, the N⁶ -amineof adenine and the N² -amine of guanine are protected. Suitable methodsare essentially as described (Gilliam, "Anal. Biochem." 157:199 (1986);Gallo-Rodriguez, "J. Med. Chem." 37:636 (1994); Maillard, "J. Pharm.Sci." 83:46 (1994)).

The exemplary reaction schemes used to synthesize protected and cyclizedheterocyclic base compounds shown below utilize compound (30) whereB=cytosine. ##STR44## wherein R³ is as defined above. Either procedureis readily adapted to compounds in which the heterocyclic base is, forinstance, adenine, guanine, 2,6-diaminopurine or 2-aminopurine where anexocyclic amine is linked to the base. The cyclic esters may comprise asingle isomer or a scalemic mixture at the phosphorus atom. Lowtemperature reaction conditions (lower than about -20°, e.g., about -20°to about -40° C. or about -40° to about -80° C.) may tend to favorsingle isomer products, while reaction at higher temperatures (aboveabout -20°, e.g. -20° to 40° C.) may result in a scalemic mix. Thepivaloyloxymethyl ester synthesis may yield a scalemic mixture at thephosphorus atom. When and if a scalemic mixture is obtained, the isomersare conveniently separated by HPLC, although the mixture can be used,for example, as a synthetic intermediate or as an active antimicrobialagent, without resolution at the #6 site.

A method to obtain heterocyclic bases comprising the C(O)R³ protectinggroup is accomplished as follows using the acyl chloride (R³ C(O)Cl)using compound (30) as an example ##STR45## wherein Tr is the hydroxylprotecting group trityl. The detritylation step is accomplished by acidtreatment, such as 80% acetic acid at about 20° to 80° C. for 4-24hours. The R³ moiety is removed using a Lewis acid such as TMSBr toyield the free phosphonate.

Phosphonate compounds comprising a C₂ -C₂₀ 1-acyloxy-1-alkyl or a C₄-C₂₀ 1-acyloxy-1-alkyl-1-aryl ester group are prepared as follows##STR46## wherein R³ is defined above.

The amine protecting group =CRN(R)₂ is incorporated into an exocyclicamine to yield protected heterocyclic base compounds as follows##STR47## Exemplary R³ alkyl groups include methyl, ethyl, propyl,isopropyl, cyclopropyl, butyl, isobutyl and cyclobutyl. In general, bothR³ alkyl groups will be the same. The reaction can be carried out in dryDMF at room temperature (about 20°-30° C.) as previously described (Kerret al. "J. Pharm. Sci." 83:582 (1994); Kerr et al. "J. Med. Chem."35:1996 (1992)), or DMF can be substituted with CH₃ CN and 4 Å molecularsieves. Exemplary compounds include species where R is hydrogen, alkyl(including ethyl, propyl, isopropyl), aryl (including phenyl) oracyloxymethyl. Protected heterocyclic bases where R⁴ is hydrogen arestable under neutral anhydrous conditions and are generally labile underacidic aqueous conditions. When R⁴ is methyl, the protecting group ismore stable to aqueous acidic or basic conditions.

Compounds containing a protected heterocyclic base and 1 or 2 aminoacids, dipeptides or oligopeptides attached to the phosphorus atom viaan amidate linkage are obtained as described for synthesis ofbis-amidate or amidate-ester compounds.

Table 7 lists R³ ester and Y amidate moieties that can be bonded viaoxygen or directly, respectively, to the phosphorus atom. Esters ofstructures 1-5, 8-10 and 16, 17, 19-22 are synthesized by reacting anucleotide analogue having a free hydroxyl with the corresponding halide(chloride or acyl chloride and the like) and N,N-dicylohexyl-N-morpholine carboxamidine (or another base such as DBU,triethylamine, CsCO₃, N,N-dimethylaniline and the like) in DMF (or othersolvent such as acetonitrile or N-methylpyrrolidone.) Esters ofstructures 5-7, 11, 12, 21, and 23-26 are synthesized by reaction of thealcohol or alkoxide salt (or the corresponding amines in the case ofcompounds such as 13, 14 and 15) with the monochlorophosphonate ordichlorophosphonate or another activated phosphonate.

                  TABLE 7                                                         ______________________________________                                        1.    --CH.sub.2 --C(O)--N(R.sup.15).sub.2 *                                  2.    --CH.sub.2 --S(O)(R.sup.15)                                             3.    --CH.sub.2 --S(O).sub.2 (R.sup.15)                                      4.    --CH.sub.2 --O--C(O)--CH.sub.2 --C.sub.6 H.sub.5                        5.    3-cholesteryl                                                           6.    3-pyridyl                                                               7.    N-ethylmorpholino                                                       8.    --CH.sub.2 --O--C(O)--C{hd 6H.sub.5                                     9.    --CH.sub.2 --O--C(O)--CH.sub.2 CH.sub.3                                 10.   --CH.sub.2 --O--C(O)--C(CH.sub.3).sub.3                                 11.   --CH.sub.2 --CCl.sub.3                                                  12.   --C.sub.6 H.sub.5                                                       13.   --NH--CH.sub.2 --C(O)O--CH.sub.2 CH.sub.3                               14.   --N(CH.sub.3)--CH.sub.2 C(O)O--CH.sub.2 CH.sub.3                        15.   --NHR.sup.3                                                             16.   --CH.sub.2 --O--C(O)--C.sub.10 H.sub.15                                 17.   --CH.sub.2 --O--C(O)--CH(CH.sub.3).sub.2                                18.   --CH.sub.2 --C#H(OC(O)CH.sub.2 R.sup.15)--CH.sub.2 --(OC(O)CH.sub.2           R.sup.15)*                                                                     ##STR48##                                                              20.                                                                                  ##STR49##                                                                     ##STR50##                                                                     ##STR51##                                                                     ##STR52##                                                                     ##STR53##                                                                     ##STR54##                                                                     ##STR55##                                                              ______________________________________                                         *-Each R.sup.15 is the same or different (includes methyl, ethyl, propyl,     isopropyl and tbutyl).                                                        #-chiral center is (R), (S) or racemate.                                 

Other esters that are suitable for use herein are described in EP632,048.

To the extent any compound of this invention cannot be produced by oneof the foregoing schemes other methods will be apparent to the artisanreferring to conventional methods (see for instance Liotta et al."Compendium of Organic Synthesis Methods" (John Wiley & Sons, New York),Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T.Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and LeroyWade, 1977; Vol. 4, Leroy G. Wade, Jr., 1980; Vol. 5, Leroy G. Wade,Jr., 1984; and Vol. 6, Michael B. Smith; March, J., "Advanced OrganicChemistry, Third Edition", (John Wiley & Sons, New York, 1985); as wellas "Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiencyin Modern Organic Chemistry. In 9 Volumes", Barry M. Trost,Editor-in-Chief (Pergamon Press, New York, 1993 printing).

All citations are hereby expressly incorporated by reference. Thefollowing examples are illustrative and do not limit the scope of thisinvention.

EXAMPLE 1 Synthesis of Diisopropyl (4,6-di-O-acetyl-2,3-dideoxy-α-and-β-D-erythro-hex-2-enopyranosyl) phosphonate (22) (21)→(22)

To solution of (2.72 g,10 mmol) of3,4,6-tri-O-acetyl1,2-dideoxy-D-arabino-hex-1-enopyranose(3,4,6-tri-O-acetyl-D-glucal) and (3.12 g, 15 mmol) oftriisopropylphosphite in dry toluene (20 ml) was added boron trifluorideetherate (0.18 ml, 1.5 mmol). The mixture was heated to 100° C. for 4 h.The solvent was removed, residue was codistilled three times withtoluene (50 ml), and purified by column chromatography on silica gel,eluting with hexane-ethyl acetate 4:1 to afford (22) as a colorless oil(3.145 g, 83%). (Modified procedure from H. Paulsen, "J. Thiem: Chem.Ber." 106:3850-3876 (1973).)

EXAMPLE 2 Synthesis of Diisopropyl (2,3-dideoxy-α-and-β-D-erythro-hex-2-enopyranonate (23) (22)→(23)

Compound (23), (3.79 g, 10 mmol) was dissolved in saturated solution ofNH₃ in MeOH and stirred at ambient temperature for 6 h. The solvent wasremoved and the residue codistilled with toluene. Drying afforded (23),2.94 g as a mixture of α and β anomers 1:1 (100%).

EXAMPLE 3 Synthesis ofDiisopropyl-(2,3-dideoxy-6-triphenylmethyl-α-D-erythro-hex-2-enopyranosyl)phosphonate (24a) and Diisopropyl (2,3-dideoxy-6-O-triphenylmethyl-β-D-erythro-hex-2-enopyranosyl) phosphonate (24b) ##STR56##

To a solution of compound (23), (2.94 g, 10 mmol) in toluene (50 ml) wasadded triphenylmethylchloride (2.79 g, 10 mmol) and pyridine (3 ml).Mixture was stirred at ambient temperature for 24 h. Toluene was added(150 ml) and the mixture was extracted with 1M hydrochloric acid, asaturated solution of NaHCO₃ and water. The organic phase was dried(MgSO₄), filtered, and evaporated to leave an oil which was purified bycolumn chromatography on silica gel, eluting with hexane-ethyl acetate(5:1, 3:1) to give pale yellow oils of (24a) ((α anomer, 2.09 g, 39%)and (24b) (β anomer, 2.46 g, 46%): (24a): ¹ H NMR (CDCl₃) δ 6 1.28 (m,12H), 3.40 (m,2H), 3.53 (m,1H), 4.22 (m,1H), 4.53 (d, J=17.5 Hz, 1H),4.76 (m, 1H), 5.94 (,2H), 7.28 (m, 15H). (24b): ¹ H NMR (CDCl₃) δ 1.32(m, 12H), 3.27 (m, 1H), 3.35 (m, 1H), 4.07 (brs, 1H), 4.21 (m, 1H), 4.42(m, 1H), 4.77 (m, 1H), 5.88 (m, 1H), 6.02 (m, 1H), 7.28 (m, 15H).

EXAMPLE 4 Synthesis of Diisopropyl 4-(N⁴-benzoylcytosin-1-yl)-2,3-dideoxy-6-O-triphenylmethyl-β-D-threo-hex-2-enopyranosyl!phosphonate (25') ##STR57##

To a 0° C. stirred solution of triphenylphosphine (0.786 g, 3 mmol) inanhydrous THF (20 ml) under dry nitrogen atmosphere, was added diethylazodicarboxylate (0.522 g, 3 mmol). After the mixture was stirred for 30min, compound (24b) was added followed by N⁴ -benzoylcytosine. After themixture was stirred at 0° C. for 24 h, the solvent was removed and theresidue was purified by column chromatography on silica gel (CH₂ Cl₂--MeOH) to give (25') (0.557 g, 38%): ¹ H NMR (CDCl₃) δ 1.39 (m,12H),3.14 (m, 2H), 3.92 (m, 1H), 4.62 (m, 1H), 4.85 (m,2H), 5.53 (m, 1H),6.05 (m, 1H), 6.42 (d, J=7.2 1H), 7.10-7.60 (m, 20H), 7.92 (d, J=7.21H).

EXAMPLE 5 Synthesis of Diisopropyl4-(cytosin-1-yl)-2,3-dideoxy-6-O-triphenyl-methyl-β-D-threo-hex-2-enopyranosyl!phosphonate (25") ##STR58##

Compound (25') (0.557 g, 0.76 mmol) was treated with saturated solutionof NH₃ in MeOH (20 ml) for 16 h at ambient temperature. The solvent wasremoved and product was purified by silica gel chromatography to give(25") (0.38 g, 80%): ¹ H NMR (CDCl₃) δ 1.40 (m, 12H), 3.32 (m, 1H), 3.48(m, 1H), 4.04 (m, 1H), 4.72 (d, J=17.5 Hz1H), 5.12 (m, 2H), 5.65 (m,1H), 5.82 (d, J=7.1 1H), 6.20 (m, 1H), 6.30 (m, 1H), 7.1-7.6 (m, 15H),7.83 (d, J=7.1 1H).

EXAMPLE 6 Synthesis of Diisopropyl4-(cytosin-1-yl)-2,3-dideoxy-β-D-threo-hex-2-enopyranosyl! phosphonate(29') ##STR59##

Compound (25") (0.38 g, 0.6 mmol) was dissolved in 80% acetic acid andstirred at ambient temperature for 16 h. The solvent was removed andproduct isolated by silica gel chromatography to give (29') (0.195 g,83%): ¹ H NMR (CDCl₃) δ 1.35(m, 12 H), 3.28 (m, 1H), 3.56 (m,1H), 3.88(m, 1H), 4.58 (d, J=18 Hz, 1H), 4.77 (m, 2H), 5.40 (m, 1H), 5.79 (d,J=7.2 Hz, 1H), 6.04 (m, 1H), 6.34 (m, 1H), 7.98 (d, J=7.2 Hz, 1H).

EXAMPLE 7 Synthesis of 4-(cytosin-1-yl)-2,3-dideoxy-β-D-threo-hex-2-enopyranosylphosphonic acid (30") ##STR60##

To a solution of (29') (0.195 g, 0.5 mmol) in acetonitrile (5 ml) wasadded 2,4-lutidine (0.6 ml, 5 mmol) and trimethylbromosilane (0.66 ml, 5mmol) and the mixture was stirred for 24 h. Solvent was evaporated andthe dry residue was coevaporated with methanol (10 ml). The residue wasdissolved in water (5 ml) and applied on Dowex 1 AcO⁻⁻ form! (20 ml),eluting with water (300 ml) and 0.1M acetic acid. Product-containingfractions were collected, evaporated and the residue was precipitatedfrom H₂ O-acetonitrile to give white precipitate of (30') (0.136 g,90%): mp 250°-300° C. decomp.; ¹ H NMR (CDCl₃) δ 3.50-3.74 (m, 2H), 4.01(m, 1H), 4.58 (dd J=18.0, 1.83 Hz, 1H), 5.29 (m, 1H), 5.96 (m, 1H), 6.18(d, J=7.9 Hz, 1H), 6.53 (m, 1H), 8.26 (d, J=7.9 Hz, 1H); HRMS, 304.0692(M+H -glycerol), calcd for C₁₀ H₁₅ N₃ O₆ P 304.0698.

EXAMPLE 8 Synthesis of Diisopropyl 4-(cytosin-1-yl)-2,3-dideoxy-β-D-threo-hexopyranosyl! phosphonate (31') ##STR61##

Compound (29') (0.195 g, 0.5 mmol) was dissolved in methanol (10 ml),catalytic amount of 10%Pd/C was added and mixture was hydrogenated by H₂under 200 Psi for 4 hours. Then mixture was filtered through celite andevaporation afforded 0.195 g of (31') as a white solid: ¹ H NMR (CDCl₃)δ 1.27 (m, 12 H), 1.75 (m, 2H), 2.00 (m. 2H), 3.49 (m, 1H), 3.67 (m,1H),3.88 (m, 2H), 4.76 (m, 2H), 4.97 (m, 1H), 5.71 (m, 1H), 8.14 (m, 1H).

EXAMPLE 9 Synthesis of4-(cytosin-1-yl)-β-D-threo-hexopyranosylphosphonic acid (32') ##STR62##

To a solution of (32') (0.195 g, 0.49 mmol) in acetonitrile (5 ml) wasadded 2,4-lutidine (0.6 ml, 5 mmol) and trimethylbromosilane (0.66 ml, 5mmol) and the mixture was stirred for 24 h. Solvent was evaporated anddry residue was coevaporated with methanol (10 ml). The residue wasdissolved in water (5 ml) and applied on Dowex 1 AcO-form! (20 ml),eluting with water (300 ml) and 0.1M acetic acid. Product containingfractions were collected, evaporated and residue was precipitated fromH₂ O-acetonitrile to give a white precipitate of (32') (0.136 g, 90%):mp 217° C.; ¹ H NMR (CDCl₃) δ 1.71 (m, 2H), 2.00 (m, 2H), 3.49 (m, 2H),3.73 (m, 1H), 3.91 (m, 1H), 4.59 (m, 1H), 6.05 (d, J=8.0 Hz, 1H), 8.51(d,J=8.0 Hz, 1H). HRMS, 306.0859 (M+H -glycerol), calcd for C₁₀ H₁₇ N₃0₆ P 306.0855.

EXAMPLE 10 Synthesis of Diisopropyl 4-(N⁴-benzoylcytosin-1-yl)-2,3-dideoxy-6-O-triphenylmethyl-α-D-threo-hex-2-enopyranosyl!phosphonate (26') ##STR63## Starting from compound (24a) and repeatingthe process of example 4, compound (26') was prepared: ¹ H NMR (CDCl₃) δ1.38 (m, 12H), 3.15 (m, 2H), 3.95 ((m, 1H), 4.62 (m, 1H), 4.85 (m, 2H),5.52 (m, 1H), 6.08 (m,2H), 6.40 (d, J=7.8Hz 1H), 7.1-7.4 (m, 20H), 7.92(d, J=7.8 1H). EXAMPLE 11 Synthesis of Diisopropyl4-(cytosin-1-yl)-2,3-dideoxy-6-O-triphenyl-methyl-D-threo-hex-1-enopyranosyl! phosphonate (27') ##STR64##

Starting from compound (26') and repeating the procedure from example 5,compound (27') was prepared: ¹ H NMR (CDCl₃) δ 1.32 (m,12H), 2.17(m,1H), 2.77 (m,1H), 3.29 (m, 2H), 4.21 (m, 1H), 4.74 (m, 2H), 5.31 (d,J=7.2 Hz 1H), 5.44 (d, J=7.3 Hz 1 Hz), 5.99 (m, 1H), 7.25 (m, 15H), 7.82(d, J=7.3 1H).

EXAMPLE 12 Synthesis of Diisopropyl4-(cytosin-1-yl)-2,3-dideoxy-D-threo-hex-1-enopyranosyl! phosphonate(27") ##STR65##

Starting from compound (27') and repeating the procedure from example 6,compound (27") was prepared: ¹ H NMR (CDCl₃) δ 1.31 (m, 12H), 2.23 (m,1H), 2.93(m, 1H), 3.33 (m, 1H), 3.73 (m, 1H), 4.04 (m 1H), 4.67 (m, 2H),5.36 (m, 1H), 5.74 (d, J=7.5 Hz 1H), 6.12 (m, 1H), 7.31 (d, J=7.5 Hz,1H).

EXAMPLE 13 Synthesis of4-(cytosin-1-yl)-2,3-dideoxy-D-threo-hex-1-enopyranosyl phosphonic acid(28') ##STR66##

Starting from compound (27") and repeating the procedure from example 7,compound (28') was prepared: mp 290° C.: ¹ H NMR (CDCl₃) δ 2.12 (m, 1H),2.84 (m, 1H), 3.51 (m, 1H), 3.68 (m, 1H), 4.02 (s, 1H), 5.07 (d, J=7.3Hz 1H), 5.69 (d, J=9.52 Hz 1H), 6.06 (d, J=8.05 Hz 1H), 7.56 (d, J=8.05Hz 1H). HRMS, 304.0697 (M+H -glycerol), calcd for C₁₀ H₁₀ N₃ O₆ P306.0698

EXAMPLE 14 Synthesis of 4-(cytosin-1-yl)-2,3-dideoxy-β-L-threo-hex-2-enopyranosyl phosphonate (60) ##STR67##

Starting from (59)3,4,6-tri-O-acetyl-1,2-dideoxy-L-arabino-hex-1-enopyranose(3,4,6-tri-O-acetyl-L-glucal), and repeating the procedures fromexamples 1 to 7, compound (60) was prepared: mp 250°-300° C. decomp; ¹ HNMR (CDCl₃) δ 3.40-3.64 (m, 2H), 3.93 (m, 1H), 4.50 (d J=18.1 Hz 1H),5.22 (m, 1H), 5.88 (m, 1H), 6.06 (d, J=7.5 Hz 1H), 6.45 (m, 1H), 8.12(d, J=7.5 Hz, 1H).

EXAMPLE 15 Synthesis of4-(cytosin-1-yl)-2,3-dideoxy-L-threo-hex-1-enopyranosylphosphonic acid(61) ##STR68##

Starting from compound (59) and repeating the procedures from examples 1to 3, and from 10 to 13, compound (61) was prepared: mp 290° C.; ¹ H NMR(CDCl₃) δ 2.14 (m, 1H), 2.91 (m, 1H), 3.53 (m, 1H), 3.72 (m, 1H), 4.08(m, 1H), 5.12 (d, J=8.1 Hz 1H), 5.76 (m, 1H), 6.05 (d, J=7.5 Hz 1H),7.56 (d, J=7.5 Hz 1H).

EXAMPLE 16 Synthesis of Diisopropyl2,3,6-trideoxy-α-and-β-L-erythro-hex-2-enopyranosylphosphonate (63)##STR69##

Starting from 3,4-di-O-acetyl-1,2,6-trideoxy-L-arabino-hex-1-enopyranose(3,4-di-O-acetyl-6-deoxy-L-glucal) (62) and repeating the proceduresfrom examples 1 and 2 compound (63) was made as a mixture of α and βanomers: ¹ H NMR (CDCl₃) δ 1.25 (m,15H), 3.32 (m, 1H), 3.82 (m, 1H),4.38 (m, 1H), 4.72 (m, 2H), 5,98 (m, 2H).

EXAMPLE 17 Synthesis of4-(cytosin-1-yl)-2,3,6-trideoxy-β-L-threo-hex-2-enopyranosylphosphonicacid (64) and4-(cytosin-1-yl)-2,3,6-trideoxy-L-threo-hex-1-enopyranosylphosphonicacid (65) ##STR70##

Starting from mixture of anomers of compound (63) and repeatingprocedures from examples 4, 5, and 7, compounds (64) and (65) wereprepared. The α and β anomers were separated after deprotection step(example 5) by silica gel chromatography: (64): mp 288° C.; ¹ H NMR(CDCl₃) δ 1.03 (d, J=6.54 Hz, 3H), 4.03 (m, 1H), 4.50 (d, J=17,58 Hz1H), 5.12 (m, 1H), 5.94 (m, 1H), 6.04 (d, J=7.3 Hz 1H), 6.43 (m, 1H),8.05 (d, J=7.3). HRMS, 288.0756 (M+H -glycerol), calcd for C₁₀ H₁₅ N₃ O₅P 288.0749. (65): mp 285° C.; ¹ H NMR (CDCl₃) δ 1.16 (d, J=6.3 Hz 3H),2.20 (m, 1H), 2.88 (m, 1H), 4.21 (m, 1H), 5.04 (d, J=7.8 Hz 1H), 5.76(m, 1H), 6.06 (d, J=7.8 Hz 1H), 7.54 (d, J=7.8 Hz 1H); HRMS, 288.0754(M+H -glycerol), calcd for C₁₀ H₁₅ N₃ O₅ P 288.0749.

EXAMPLE 18 Synthesis of4-(adenine-9-yl)-2,3-dideoxy-D-threo-hex-1-enopyranosyl phosphonic acid(28") ##STR71##

Starting from compound (24a) and using the procedures from examples 4,5, 6 and 7 (except instead of N⁴ -benzoylcytosine, N⁶ -benzoyladeninewas used) compound (28") was prepared: ¹ H NMR (CDCl₃) δ 2.43 (m, 1H),3.08 (m, 1H), 3.33 (m, 1H), 3.61 (m, 1H), 4.34 (m, 1H), 5.34 (m, 1H),5.35 (d, J=6.84 Hz, 1H), 5.87 (m, 1H), 8.27 (s, 1H), 8.45 (s, 1H).

EXAMPLE 19 Synthesis of4-(adenine-9-yl)-2,3,6-trideoxy-L-threo-hex-1-enopyranosylphosphonicacid (65') ##STR72##

Starting from compound (63) and using the procedures from examples 4, 5,and 7 (except instead of N⁴ -benzoylcytosine, N⁶ -benzoyladenine wasused) compound (65') was prepared: mp 151° C.: ¹ H NMR (CDCl₃) δ 1.00(d, J=6,35 Hz 3H), 2.37 (m, 1H), 2.99 (m, 1H), 4.37 (m, 1H), 4,99 (d,J=6,84 Hz 1H), 5.78 (m, 1H), 8.10 (s, 1H), 8.24 (s, 1H) HRMS, 312.0862(M+H -glycerol), calcd for C₁₁ H₁₅ N₅ O₄ P 312.0861.

EXAMPLE 20 Synthesis of4-(thymin-1-yl)-2,3,6-trideoxy-α-L-threo-hex-2-enopyranosyl phosphonicacid (66)4-(thymin-1-yl)-2,3,6-trideoxy-β-L-threo-hex-2-enopyranosylphosphonicacid (64') and4-(thymin-1-yl)-2,3,6-trideoxy-L-threo-hex-1-enopyranosylphosphonic acid(65") ##STR73##

Starting from compound (63) and using procedures from examples 4, 5, and7 (except instead of N⁴ -benzoylcytosine, N³ -benzoylthymine was used).The mixture was separated after deprotection of base (example 5) andeach isolated compound was deprotected by trimethylbromosilane (example7): (66): ¹ H NMR (CDCl₃) δ 1.00 (d, J=6.59 Hz 3H), 1.86 (s, 3H), 3.92(m, 1H), 4.44 (m, 1H), 4.97 (m, 1H), 5.82 (m, 1H), 6.53 (mm, 1H), 7.41(s, 1H). (64'): ¹ H NMR (CDCl₃) δ 1.06 (d, J=5.86 Hz 3H), 1.87 s, 3H),3.99 (m, 1H), 4.41 (m, 1H), 4.99 (m, 1H), 5.86 (m, 1H), 6.48 (m, 1H),7.38 (s, 1H); HRMS 325.0578 (M+H -glycerol), calcd for C₁₁ H₁₅ N₂ O₆ NaP325.0565. (65"): ¹ H NMR (CDCl₃) δ 1.17 (d, J=1.17 Hz 3H), 1.88 (d,J=0.99 Hz 3H), 2.16 (m, 1H), 2.83 (m, 1H), 4.16 (m, 1H), 4.91 (m 1H),5.61 (m, 1H), 7.42 (d, J=0.98 Hz 1H); HRMS 325.0573 (M+H -glycerol),calcd for C₁₁ H₁₅ N₂ O₆ NaP 325.0578.

EXAMPLE 21

Compounds made in the foregoing examples were assayed for inhibitoryeffect against human CMV using the standard plaque inhibition assay(Lurain, "J. Vir." 66:7146-7152 (1992)). The cells used for the toxicityassay were normal human dermal fibroblasts. The results are shown inTable 8 below.

                  TABLE 8                                                         ______________________________________                                        Compound Tested IC.sub.50 (μM)                                                                      CC.sub.50 (μM)                                    ______________________________________                                        (30)            10       >1000                                                 (28')          40       >1000                                                 (32')          80       >1000                                                (64)            200      >1000                                                (65)            300      >1000                                                ______________________________________                                    

A related known compound, HPMPC, was more potent but also more toxicthan the best compound of the invention tested here, exhibiting an IC₅₀of 0.5 micromolar and a CC₅₀ of 200 micromolar.

The claims shall be construed to exclude any subject matter that, at thedate of the invention, would not have been patentable under applicablestatutory and judicial authority.

We claim:
 1. A method comprising(a) providing a compound havingstructure (I) ##STR74## (b) reacting the compound of structure (I) withP(OPRT)₃ in the presence of a Lewis Acid; and (c) recovering from thereaction mixture of step (b) a compound having structure (II) ##STR75##wherein PRT is a protecting group and Z is CH₂ OPRT, halo substituted C₁-C₂ alkyl, CH═CH₂, C.tbd.CH, --CH₂ N₃, CH₃, or H.